bluuebunny/crossref_metadata_2025 huggingface dataset:
Life Cycle Assessment of a Prospective Technology for Building-Integrated Production of Broccoli Microgreens
Authors: Parkes Michael G. , Cubillos Tovar Julieth P. , Dourado Filipe , Domingos Tiago , Teixeira Ricardo F. M.
Published: August 2022

Indoor Vertical Farms (IVF) can contribute to urban circular food systems by reducing food waste and increasing resource use efficiency. They are also known for high energy consumption but could potentially be improved by integration with buildings. Here, we aim to quantify the environmental performance of a prospective building-integrated urban farm. We performed a Life Cycle Assessment for a unit installed in a university campus in Portugal, producing broccoli microgreens for salads. This technology integrates IVF, product processing and Internet of Things with unused space. Its environmental performance was analyzed using two supply scenarios and a renewable energy variation was applied to each scenario. Results show that the IVF system produces 7.5 kg of microgreens daily with a global warming potential of 18.6 kg CO2e/kg in the case of supply direct on campus, or 22.2 kg CO2e/kg in the case of supply off campus to retailers within a 10-km radius. Consistently in both scenarios, electricity contributed the highest emission, with 10.03 kg CO2e/kg, followed by seeds, with 4.04 kg CO2e/kg. The additional use of photovoltaic electricity yields a reduction of emissions by 32%; an improvement of approximately 16% was found for most environmental categories. A shortened supply chain, coupled with renewable electricity production, can contribute significantly to the environmental performance of building-integrated IVF.
Sensitivity of the 4–10-Day Planetary Wave Structures in the Middle Atmosphere to the Solar Activity Effects in the Thermosphere
Authors: Koval Andrey V. , Gavrilov Nikolai M. , Didenko Ksenia A. , Ermakova Tatiana S. , Savenkova Elena N.
Published: August 2022

Numerical simulation of the general atmospheric circulation was performed to estimate changes in amplitudes of the westward-travelling planetary waves (PWs) at altitudes from the Earth’s surface up to 300 km under different solar activity (SA) levels. The three-dimensional nonlinear mechanistic model of circulation of the middle and upper atmosphere “MUAM” was used. The atmospheric general circulation and PW amplitudes were calculated based on ensembles containing 16 model runs for conditions corresponding to low and high SA. PWs having periods of 4–10 days were considered. Comparison with the data of digital ionosondes showed that the MUAM model is capable of reproducing the considered PW modes at thermospheric heights. It is shown that under high SA conditions, PW amplitudes are significantly larger in the thermosphere and smaller in the middle atmosphere. The observed PW structures are influenced not only by changes in atmospheric refractive index and Eliassen–Palm flux but also by varying PW reflection in the lower thermosphere, which can change proportions of the wave energy transferred from the lower atmosphere to the upper layers and reflected downwards.
Moisture Sources for the Precipitation of Tropical-like Cyclones in the Mediterranean Sea: A Case of Study
Authors: Coll-Hidalgo Patricia , Pérez-Alarcón Albenis , Nieto Raquel
Published: August 2022

Tropical-like cyclones (TLCs) are hybrid low-pressure systems formed over the Mediterranean Sea, showing the characteristics of tropical and extratropical cyclones. The literature review revealed that several studies have focused on determining the physical mechanisms that favour their formation; however, their rainfall has received little attention. In this study, we attempted to identify the origin of the precipitation produced by TLCs through a Lagrangian approach based on the analysis of moisture sources for the TLC Qendresa from 6 to 9 November 2014. For the Lagrangian analysis, we used the trajectories of air parcels from the global outputs of the FLEXPART model fed by the ERA-5 reanalysis provided by the European Centre for Medium-Range Weather Forecast and backtracked those parcels that precipitated within the outer radius of the storm up to 10 days. Our results showed that the moisture mainly came from the western Mediterranean Sea, Northern Africa, the central Mediterranean Sea, Western Europe, the eastern North Atlantic, and the eastern Mediterranean Sea with contributions of 35.09%, 27.6%, 18.62%, 10.40%, 6.79%, and 1.5%, respectively. The overall large-scale conditions for the genesis of Qendresa agreed with previous climatological studies. Therefore, our findings contribute to the understanding of precipitation associated with TLCs. Future studies will focus on a climatological analysis of the origin of rainfall produced by these hybrid cyclones.
Electric Field Variations Caused by Low, Middle and High-Altitude Clouds over the Negev Desert, Israel
Authors: Yaniv Roy , Yair Yoav
Published: August 2022

Ground-based measurements of the electric field from a station located in the arid Negev region of southern Israel have been conducted continuously since 2013. We present here results of observations of the electric field (Potential Gradient, PG) variability during 22 cloudy days, with varying cloud types and cloud base heights, and compare the measured values with the mean fair-weather PG. The results show an increase of PG (~+10 to +70 V m−1) from mean fair weather values during times of low clouds. During times of mid-altitude (alto) clouds or during a superposition of low and high clouds, there were small departures in the PG values (~0 to −30 V m−1) compared to mean fair weather PG values. During times of high-altitude cirrus clouds there is a clear decrease of the PG (~−40 to −90 V m−1). The data was compared with the Israeli meteorological service cloud data and with MODIS 7 satellite cloud top height maps. In addition, AERONET aerosol optical depth values and wind speed magnitude from a local meteorological station were analyzed.
StEduCov: An Explored and Benchmarked Dataset on Stance Detection in Tweets towards Online Education during COVID-19 Pandemic
Authors: Hamad Omama , Hamdi Ali , Hamdi Sayed , Shaban Khaled
Published: August 2022

In this paper, we present StEduCov, an annotated dataset for the analysis of stances toward online education during the COVID-19 pandemic. StEduCov consists of 16,572 tweets gathered over 15 months, from March 2020 to May 2021, using the Twitter API. The tweets were manually annotated into the classes agree, disagreeor neutral. We performed benchmarking on the dataset using state-of-the-art and traditional machine learning models. Specifically, we trained deep learning models—bidirectional encoder representations from transformers, long short-term memory, convolutional neural networks, attention-based biLSTM and Naive Bayes SVM—in addition to naive Bayes, logistic regression, support vector machines, decision trees, K-nearest neighbor and random forest. The average accuracy in the 10-fold cross-validation of these models ranged from 75% to 84.8% and from 52.6% to 68% for binary and multi-class stance classifications, respectively. Performances were affected by high vocabulary overlaps between classes and unreliable transfer learning using deep models pre-trained on general texts in relation to specific domains such as COVID-19 and distance education.
Initial Healing Effects of Platelet-Rich Plasma (PRP) Gel and Platelet-Rich Fibrin (PRF) in the Deep Corneal Wound in Rabbits
Authors: Choi Seo-Young , Kim Soochong , Park Kyung-Mee
Published: August 2022

Platelet concentrates (PCs), including platelet-rich plasma (PRP) gel and platelet-rich fibrin (PRF), are autologous blood-derived biomaterials containing numerous growth factors. This study aimed to evaluate the initial healing effects of PRP gel and PRF on deep corneal wounds. Thirty-three eyes from New Zealand white rabbits were divided into four groups: group 1, lamellar keratectomy (LK); group 2, LK + commercial porcine small intestinal submucosal membrane (SIS); group 3, LK + SIS + PRP gel; and group 4, LK + SIS + PRF. Postoperative clinical and histological findings were observed for eight weeks. Group 1 showed no neovascularization during the observation period, and incompletely recovered with a thin cornea. Group 2 showed active healing through neovascularization, and a thick cornea was regenerated through the sufficient generation of myofibroblasts. Although group 3 showed a healing effect similar to that of group 2, angiogenesis and subsequent vessel regression were promoted, and corneal opacity improved more rapidly. In group 4, angiogenesis was promoted during initial healing; however, the incidence of complications, such as inflammation, was high, and myofibroblasts were hardly generated in the corneal stroma, which adversely affected remodeling. In conclusion, while PRP gel is a safe surgical material for promoting remodeling through vascular healing and myofibroblast production in deep corneal wounds, the use of PRF is not recommended.
In Vitro Modeling of the Blood–Brain Barrier for the Study of Physiological Conditions and Alzheimer’s Disease
Authors: Schreiner Thomas Gabriel , Creangă-Murariu Ioana , Tamba Bogdan Ionel , Lucanu Nicolae , Popescu Bogdan Ovidiu
Published: August 2022

The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, a deeper understanding of the BBB’s structure and function is mandatory for a better knowledge of neurodegenerative disorders and the development of effective therapies. Because studying the BBB in vivo imposes overwhelming difficulties, the in vitro approach remains the main possible way of research. With many in vitro BBB models having been developed over the last years, the main aim of this review is to systematically present the most relevant designs used in neurological research. In the first part of the article, the physiological and structural–functional parameters of the human BBB are detailed. Subsequently, available BBB models are presented in a comparative approach, highlighting their advantages and limitations. Finally, the new perspectives related to the study of Alzheimer’s disease with the help of novel devices that mimic the in vivo human BBB milieu gives the paper significant originality.
Prediction of Aggregation of Biologically-Active Peptides with the UNRES Coarse-Grained Model
Authors: Biskupek Iga , Czaplewski Cezary , Sawicka Justyna , Iłowska Emilia , Dzierżyńska Maria , Rodziewicz-Motowidło Sylwia , Liwo Adam
Published: August 2022

The UNited RESidue (UNRES) model of polypeptide chains was applied to study the association of 20 peptides with sizes ranging from 6 to 32 amino-acid residues. Twelve of those were potentially aggregating hexa- or heptapeptides excised from larger proteins, while the remaining eight contained potentially aggregating sequences, functionalized by attaching larger ends rich in charged residues. For 13 peptides, the experimental data of aggregation were used. The remaining seven were synthesized, and their properties were measured in this work. Multiplexed replica-exchange simulations of eight-chain systems were conducted at 12 temperatures from 260 to 370 K at concentrations from 0.421 to 5.78 mM, corresponding to the experimental conditions. The temperature profiles of the fractions of monomers and octamers showed a clear transition corresponding to aggregate dissociation. Low simulated transition temperatures were obtained for the peptides, which did not precipitate after incubation, as well as for the H-GNNQQNY-NH2 prion–protein fragment, which forms small fibrils. A substantial amount of inter-strand β-sheets was found in most of the systems. The results suggest that UNRES simulations can be used to assess peptide aggregation except for glutamine- and asparagine-rich peptides, for which a revision of the UNRES sidechain–sidechain interaction potentials appears necessary.
Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
Authors: Pérez-Juárez Jesús , Tapia-Vieyra Juana Virginia , Gutiérrez-Magdaleno Gabriel , Sánchez-Puig Nuria
Published: August 2022

The final maturation step of the 60S ribosomal subunit requires the release of eukaryotic translation initiation factor 6 (human eIF6, yeast Tif6) to enter the pool of mature ribosomes capable of engaging in translation. This process is mediated by the concerted action of the Elongation Factor-like 1 (human EFL1, yeast Efl1) GTPase and its effector, the Shwachman-Bodian-Diamond syndrome protein (human SBDS, yeast Sdo1). Mutations in these proteins prevent the release of eIF6 and cause a disease known as Shwachman–Diamond Syndrome (SDS). While some mutations in EFL1 or SBDS result in insufficient proteins to meet the cell production of mature large ribosomal subunits, others do not affect the expression levels with unclear molecular defects. We studied the functional consequences of one such mutation using Saccharomyces cerevisiae Efl1 R1086Q, equivalent to human EFL1 R1095Q described in SDS patients. We characterised the enzyme kinetics and energetic basis outlining the recognition of this mutant to guanine nucleotides and Sdo1, and their interplay in solution. From our data, we propose a model where the conformational change in Efl1 depends on a long-distance network of interactions that are disrupted in mutant R1086Q, whereby Sdo1 and the guanine nucleotides no longer elicit the conformational changes previously described in the wild-type protein. These findings point to the molecular malfunction of an EFL1 mutant and its possible impact on SDS pathology.
ADAR2 Protein Is Associated with Overall Survival in GBM Patients and Its Decrease Triggers the Anchorage-Independent Cell Growth Signature
Authors: Cesarini Valeriana , Silvestris Domenico Alessandro , Galeano Federica , Tassinari Valentina , Martini Maurizio , Locatelli Franco , Gallo Angela
Published: August 2022

Background: Epitranscriptomic mechanisms, such as A-to-I RNA editing mediated by ADAR deaminases, contribute to cancer heterogeneity and patients’ stratification. ADAR enzymes can change the sequence, structure, and expression of several RNAs, affecting cancer cell behavior. In glioblastoma, an overall decrease in ADAR2 RNA level/activity has been reported. However, no data on ADAR2 protein levels in GBM patient tissues are available; and most data are based on ADARs overexpression experiments. Methods: We performed IHC analysis on GBM tissues and correlated ADAR2 levels and patients’ overall survival. We silenced ADAR2 in GBM cells, studied cell behavior, and performed a gene expression/editing analysis. Results: GBM tissues do not all show a low/no ADAR2 level, as expected by previous studies. Although, different amounts of ADAR2 protein were observed in different patients, with a low level correlating with a poor patient outcome. Indeed, reducing the endogenous ADAR2 protein in GBM cells promotes cell proliferation and migration and changes the cell’s program to an anchorage-independent growth mode. In addition, deep-seq data and bioinformatics analysis indicated multiple RNAs are differently expressed/edited upon siADAR2. Conclusion: ADAR2 protein is an important deaminase in GBM and its amount correlates with patient prognosis.
Safety Profile and Outcomes of Early COVID-19 Treatments in Immunocompromised Patients: A Single-Centre Cohort Study
Authors: Biscarini Simona , Villa Simone , Genovese Camilla , Tomasello Mara , Tonizzo Anna , Fava Marco , Iannotti Nathalie , Bolis Matteo , Mariani Bianca , Valzano Antonia Grazia , Morlacchi Letizia Corinna , Donato Francesca , Castellano Giuseppe , Cassin Ramona , Carrabba Maria , Muscatello Antonio , Gori Andrea , Bandera Alessandra , Lombardi Andrea
Published: August 2022

Background: Early treatment with remdesivir (RMD) or monoclonal antibodies (mAbs) could be a valuable tool in patients at risk of severe COVID-19 with unsatisfactory responses to vaccination. We aim to assess the safety and clinical outcomes of these treatments among immunocompromised subjects. Methods: We retrospectively reviewed all nonhospitalized patients who received an early treatment with RMD or mAbs for COVID-19, from 25 November 2021 to 25 January 2022, in a large tertiary hospital. Outcomes included frequency of adverse drug reaction (ADR), duration of symptoms and molecular swab positivity, emergency department access, hospital or intensive care unit admission, and mortality in the 14 days following treatment administration. Results: Early treatments were administered to 143 patients, 106/143 (74.1%) immunocompromised, including 41 solid organ and 6 hematopoietic stem cell transplant recipients. Overall, 23/143 (16.1%) subjects reported ADRs. Median time from treatment start to SARS-CoV-2 nasopharyngeal swab negativity and symptom resolution was 10 (IQR 6–16) and 2.5 days (IQR 1.0–6.0), respectively, without differences between immunocompromised and nonimmunocompromised patients. In the 14 days after treatment administration, 5/143 patients (3.5%) were hospitalized and one died as a result of causes related to COVID-19, all of them were immunocompromised. Conclusions: RMD and mAbs have minimal ADRs and favourable outcomes in immunocompromised patients.
LLL12B, a Novel Small-Molecule STAT3 Inhibitor, Induces Apoptosis and Suppresses Cell Migration and Tumor Growth in Triple-Negative Breast Cancer Cells
Authors: Pan Li , Chen Xiang , Rassool Feyruz Virgilia , Li Chenglong , Lin Jiayuh
Published: August 2022

Persistent STAT3 signaling plays a pivotal role in human tumor malignancy, including triple-negative breast cancer (TNBC). There are few treatment options currently available for TNBC; thus, given its importance to cancer, STAT3 is a potential cancer therapeutic target and is the focus of drug discovery efforts. In this study, we tested a novel orally bioavailable small-molecule STAT3 inhibitor, LLL12B, in human MDA-MB-231, SUM159, and murine 4T1 TNBC cell lines. TNBC cells frequently expressed persistent STAT3 phosphorylation and their cell viability was sensitive to STAT3 knockdown by siRNA. LLL12B selectively inhibited the IL-6-mediated induction of STAT3 phosphorylation, but had little effect on the IFN-γ-mediated induction of STAT1 phosphorylation nor the EGF-mediated induction of ERK phosphorylation. In addition, targeting STAT3 with LLL12B induced apoptosis, reduced colony formation ability, and inhibited cell migration in TNBC cells. Furthermore, LLL12B suppressed the tumor growth of the MDA-MB-231 TNBC cells in a mammary fat pad mouse tumor model in vivo. Together, our findings support the concept that targeting persistent STAT3 signaling using the novel small-molecule LLL12B is a potential approach for TNBC therapy.
New Trends in Aging Drug Discovery
Authors: Benhamú Bellinda , Martín-Fontecha Mar , Vázquez-Villa Henar , López-Rodríguez María L. , Ortega-Gutiérrez Silvia
Published: August 2022

Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided.
TMT-Based Proteomic Analysis of Human Spermatozoa from Unexplained Recurrent Miscarriage Patients before and after Oral Antioxidant Treatment
Authors: Fernandez-Encinas Alba , Ribas-Maynou Jordi , García-Peiró Agustín , Garcia-Segura Sergio , Martinez-Pasarell Olga , Navarro Joaquima , Oliver-Bonet Maria , Benet Jordi
Published: August 2022

Recently, sperm quality and the presence of double-stranded breaks (DSB) has been pointed out as a possible cause of recurrent miscarriage, and the use of antioxidants has expanded as a treatment for male infertility. The aim of the present study was to analyze the proteomic effects of antioxidants on sperm from RM patients with high incidence of DSB. Proteomic analysis was performed using a tandem mass tag labeling technique, and subsequently compared with the PANTHER database for DEPs, and the STRING database for protein–protein interactions (PPI). Differentially expressed proteins (DEPs) both before and after antioxidant oral treatment were identified. PPI involving DEPs clustered into networks related to cell metabolism, cytoskeleton, and DNA damage. Results show that the sperm proteomic profiles before and after antioxidant treatment do not significantly differ from each other. However, some DEPs found after the antioxidant treatment shifted towards a DEPs profile typical of fertile donors. This indirect measurement suggests an improvement caused by antioxidants on the expression of several proteins. Among them were proteins involved in sperm DNA remodeling (LMO7, MMP28, BNC2, H2B, and PRDM2). The results presented here represent the first approach in the analysis and repair of the proteomic change caused by antioxidants in recurrent miscarriage patients, elucidating biomarkers that may be useful for the diagnosis and further sperm selection in this type of patient. Further studies should be conducted to validate the usefulness of these biomarkers in larger study groups.
The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction
Authors: Schenkl Christina , Schrepper Andrea , Heyne Estelle , Doenst Torsten , Schwarzer Michael
Published: August 2022

The antitumor treatment NVP-AEW541 blocks IGF-1R. IGF-1R signaling is crucial for cardiac function, but the cardiac effects of NVP-AEW541 are ill defined. We assessed NVP-AEW541′s effects on cardiac function and insulin response in vivo and in isolated working hearts. We performed a dose–response analysis of NVP-AEW541 in male, 3-week-old rats and assessed the chronic effects of the clinically relevant dose in adult rats. We performed glucose tolerance tests and echocardiography; assessed the expression and phosphorylation of InsR/IGF-1R and Akt in vivo; and measured substrate oxidation, contractile function, and insulin response in the isolated working hearts. NVP-AEW541 caused dose-dependent growth retardation and impaired glucose tolerance in the juvenile rats. In the adults, NVP-AEW541 caused a continuously worsening depression of cardiac contractility, which recovered within 2 weeks after cessation. Cardiac Akt protein and phosphorylation were unchanged and associated with InsR upregulation. An acute application of NVP-AEW541 in the working hearts did not affect cardiac power but eliminated insulin’s effects on glucose and fatty acid oxidation. The systemic administration of NVP-AEW541 caused dose- and time-dependent impairment of glucose tolerance, growth, and cardiac function. Because cardiac insulin signaling was maintained in vivo but absent in vitro and because contractile function was not affected in vitro, a direct link between insulin resistance and contractile dysfunction appears unlikely.
The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury
Authors: Hammarlund Maria E. , Ek C. Joakim , Akar Sukaina , Karlsson Alma , Pattanaik Bagmi , Mjörnstedt Filip , Svedin Pernilla , Ardalan Maryam , Rocha-Ferreira Eridan , Mallard Carina , Johansson Maria E.
Published: August 2022

Inflammation plays a central role in the development of neonatal brain injury. The alpha 7 nicotinic acetylcholine receptor (α7nAChR) can modulate inflammation and has shown promising results as a treatment target in rodent models of adult brain injury. However, little is known about the role of the α7nAChR in neonatal brain injury. Hypoxic-ischemic (HI) brain injury was induced in male and female C57BL/6 mice, α7nAChR knock-out (KO) mice and their littermate controls on postnatal day (PND) 9–10. C57BL/6 pups received i.p. injections of α7nAChR agonist PHA 568487 (8 mg/kg) or saline once daily, with the first dose given directly after HI. Caspase-3 activity and cytokine mRNA expression in the brain was analyzed 24 h after HI. Motor function was assessed 24 and 48 h after HI, and immunohistochemistry was used to assess tissue loss at 24 h and 7 days after HI and microglial activation 7 days after HI. Activation of α7nAChR with the agonist PHA 568487 significantly decreased CCL2/MCP-1, CCL5/RANTES and IL-6 gene expression in the injured brain hemisphere 24 h after HI compared with saline controls in male, but not female, pups. However, α7nAChR activation did not alter caspase-3 activity and TNFα, IL-1β and CD68 mRNA expression. Furthermore, agonist treatment did not affect motor function (24 or 48 h), neuronal tissue loss (24 h or 7 days) or microglia activation (7 days) after HI in either sex. Knock-out of α7nAChR did not influence neuronal tissue loss 7 days after HI. In conclusion, targeting the α7nAChR in neonatal brain injury shows some effect on dampening acute inflammatory responses in male pups. However, this does not lead to an effect on overall injury outcome.
Hemin Ameliorates the Inflammatory Activity in the Inflammatory Bowel Disease: A Non-Clinical Study in Rodents
Authors: Silva Inês , Correia Rita , Pinto Rui , Mateus Vanessa
Published: August 2022

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Currently, there is no cure, and pharmacological treatment aims to induce and maintain remission in patients, so it is essential to investigate new possible treatments. Hemin is a heme-oxygenase inducer which can confer anti-inflammatory, cytoprotective, and antiapoptotic effects; therefore, it can be considered an asset for different gastrointestinal pathologies, namely for IBD. Aim: This experiment aims to evaluate the efficacy and safety of hemin, in a chronic 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents. Methods: The induction of chronic colitis consisted of five weekly intrarectal administrations of 1% TNBS. Then, the mice were treated daily with 5 mg/kg/day or 10 mg/kg/day of hemin, through intraperitoneal injections, for 14 days. Results: Hemin demonstrated an anti-inflammatory effect through the reduction in tumor necrosis factor (TNF)-α levels, fecal calprotectin, and fecal hemoglobin. It was also found to be safe in terms of extraintestinal manifestations, since hemin did not promote renal and/or hepatic changes. Conclusions: Hemin could become an interesting tool for new possible pharmacological approaches in the management of IBD.
Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology
Authors: Sebastián-Martín Alba , Sánchez Belén G. , Mora-Rodríguez José M. , Bort Alicia , Díaz-Laviada Inés
Published: August 2022

DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.
Role of Neuropilin 1 in COVID-19 Patients with Acute Ischemic Stroke
Authors: Al-Thomali Asma W. , Al-kuraishy Hayder M. , Al-Gareeb Ali I. , K. Al-buhadiliy Ali , De Waard Michel , Sabatier Jean-Marc , Khan Khalil Atif Ali , Saad Hebatallah M. , Batiha Gaber El-Saber
Published: August 2022

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can trigger the adaptive and innate immune responses, leading to uncontrolled inflammatory reactions and associated local and systematic tissue damage, along with thromboembolic disorders that may increase the risk of acute ischemic stroke (AIS) in COVID-19 patients. The neuropilin (NRP-1) which is a co-receptor for the vascular endothelial growth factor (VEGF), integrins, and plexins, is involved in the pathogenesis of AIS. NRP-1 is also regarded as a co-receptor for the entry of SARS-CoV-2 and facilitates its entry into the brain through the olfactory epithelium. NRP-1 is regarded as a cofactor for binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2), since the absence of ACE2 reduces SARS-CoV-2 infectivity even in presence of NRP-1. Therefore, the aim of the present study was to clarify the potential role of NRP-1 in COVID-19 patients with AIS. SARS-CoV-2 may transmit to the brain through NRP-1 in the olfactory epithelium of the nasal cavity, leading to different neurological disorders, and therefore about 45% of COVID-19 patients had neurological manifestations. NRP-1 has the potential capability to attenuate neuroinflammation, blood–brain barrier (BBB) permeability, cerebral endothelial dysfunction (ED), and neuronal dysfunction that are uncommon in COVID-19 with neurological involvement, including AIS. Similarly, high NRP-1 serum level is linked with ED, oxidative stress, and the risk of pulmonary thrombosis in patients with severe COVID-19, suggesting a compensatory mechanism to overcome immuno-inflammatory disorders. In conclusion, NRP-1 has an important role in the pathogenesis of COVID-19 and AIS, and could be the potential biomarker linking the development of AIS in COVID-19. The present findings cannot provide a final conclusion, and thus in silico, experimental, in vitro, in vivo, preclinical, and clinical studies are recommended to confirm the potential role of NRP-1 in COVID-19, and to elucidate the pharmacological role of NRP-1 receptor agonists and antagonists in COVID-19.
Neutrophils, Fast and Strong
Authors: Sud’ina Galina F.
Published: August 2022

The history of medicine is also the history of our understanding of the role of neutrophils in protecting our bodies [...]
New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens
Authors: Miguel Telega Lidia , Ashouri Vajari Danesh , Stieglitz Thomas , Coenen Volker A. , Döbrössy Máté D.
Published: August 2022

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.
Potential Targets for Noninvasive Brain Stimulation on Depersonalization-Derealization Disorder
Authors: Zheng Sisi , Song Nan , Wang Sici , Ning Yanzhe , Zhu Hong , Song Mingkang , Jia Yuan , Jia Hongxiao
Published: August 2022

Introduction: Non-invasive brain stimulation seems to be beneficial for DPD patients. However, the sites used in previous studies were empirical. Exploring new stimulation locations via functional magnetic resonance imaging may improve the efficacy. Objectives: The objective was to find potential locations for non-invasive brain stimulation on the depersonalization-derealization disorder. Methods: We explored the potential brain surface regions from three pipelines: pipeline 1: activation likelihood estimation meta-analysis (five studies with 36 foci included); pipeline 2: functional connectivity analysis based on DPD-network (76 subjects included); and pipeline 3: functional connectivity analysis based on DPD regions of interest from the meta-analysis. Potential targets were the 10–20 system coordinates for brain surface regions. Results: We identified several potential brain surface regions, including the bilateral medial prefrontal cortex, dorsal lateral prefrontal cortex, superior parietal gyrus, superior temporal gyrus, and right ventrolateral prefrontal cortex as potential sites. Conclusion: Our findings of the potential stimulation targets might help clinicians optimize the application of non-invasive brain stimulation therapy in individuals with DPD.
Identification of a Novel Cuproptosis-Related Gene Signature for Prognostic Implication in Head and Neck Squamous Carcinomas
Authors: Tang Shouyi , Zhao Li , Wu Xing-Bo , Wang Zhen , Cai Lu-Yao , Pan Dan , Li Ying , Zhou Yu , Shen Yingqiang
Published: August 2022

Head and neck squamous carcinoma (HNSC) is a frequent and deadly malignancy that is challenging to manage. The existing treatment options have considerable efficacy limitations. Hence, the identification of new therapeutic targets and the development of efficacious treatments are urgent needs. Cuproptosis, a non-apoptotic programmed cell death caused by excess copper, has only very recently been discovered. The present study investigated the prognostic importance of genes involved in cuproptosis through the mRNA expression data and related clinical information of HNSC patients downloaded from public databases. Our results revealed that many cuproptosis-related genes were differentially expressed between normal and HNSC tissues in the TCGA cohort. Moreover, 39 differentially expressed genes were associated with the prognosis of HNSC patients. Then, a 24-gene signature was identified in the TCGA cohort utilizing the LASSO Cox regression model. HNSC expression data used for validation were obtained from the GEO database. Consequently, we divided patients into high- and low-risk groups based on the 24-gene signature. Furthermore, we demonstrated that the high-risk group had a worse prognosis when compared to the low-risk group. Additionally, significant differences were found between the two groups in metabolic pathways, immune microenvironment, etc. In conclusion, we found a cuproptosis-related gene signature that can be used effectively to predict OS in HNSC patients. Thus, targeting cuproptosis might be an alternative and promising strategy for HNSC patients.
FLT3-ITD Expression as a Potential Biomarker for the Assessment of Treatment Response in Patients with Acute Myeloid Leukemia
Authors: Carbonell Diego , Chicano María , Cardero Alfonso J. , Gómez-Centurión Ignacio , Bailén Rebeca , Oarbeascoa Gillen , Martínez-Señarís Diana , Franco Carolina , Muñiz Paula , Anguita Javier , Kwon Mi , Díez-Martín José Luis , Buño Ismael , Martínez-Laperche Carolina
Published: August 2022

FLT3-internal tandem duplication (ITD) analysis is not typically performed in cDNA samples and is not considered an appropriate marker for monitoring measurable residual disease (MRD). The aims of this study were to compare FLT3-ITD mutation analysis in DNA and cDNA samples at diagnosis and to demonstrate the usefulness of its expression measurement as an MRD marker after allogeneic stem cell transplantation (allo-HSCT) or FLT3 inhibitor (FLT3i) administration. A total of 46 DNA and cDNA diagnosis samples, 102 DNA and cDNA post-allo-HSCT samples from 34 patients and 37 cDNA samples from 7 patients with refractory/relapse AML treated with FLT3i were assessed for the FLT3-ITD mutation through fragment analysis. In terms of sensitivity, the analysis of cDNA was superior to that of DNA, quantifying higher allelic ratio values in most cases at diagnosis, and thus optimizing the detection of minor clones and prognostic classification. Regarding the last sample before post-HSCT relapse, cDNA analysis anticipated relapse in most cases, unlike DNA analyses. With regard to the post-FLT3i follow-up, FLT3-ITD expression was reduced after the first FLT3i cycle when the treatment was effective, whereas it was not reduced in refractory patients. FLT3-ITD expression could be a useful additional biomarker at diagnosis and for the assessment of MRD after allo-HSCT and FLT3i in AML.
Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis
Authors: Russo Valentina , Lallo Eleonora , Munnia Armelle , Spedicato Miriana , Messerini Luca , D’Aurizio Romina , Ceroni Elia Giuseppe , Brunelli Giulia , Galvano Antonio , Russo Antonio , Landini Ida , Nobili Stefania , Ceppi Marcello , Bruzzone Marco , Cianchi Fabio , Staderini Fabio , Roselli Mario , Riondino Silvia , Ferroni Patrizia , Guadagni Fiorella , Mini Enrico , Peluso Marco
Published: August 2022

Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80–0.95 and 0.83, 95% C.I. 0.74–0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.
Palliative Efficacy of High-Dose Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Painful Non-Spine Bone Metastases: A Propensity Score-Matched Analysis
Authors: Ito Kei , Taguchi Kentaro , Nakajima Yujiro , Ogawa Hiroaki , Murofushi Keiko Nemoto
Published: August 2022

(1) Background: The superiority of stereotactic body radiotherapy (SBRT) over conventional external beam radiotherapy (cEBRT) in terms of pain palliation for bone metastases remains controversial. (2) Methods: This propensity score-matched study compared the overall pain response (OR) 3 months after radiotherapy among patients with painful (≥2 points on a 0-to-10 scale) non-spine bone metastases. Patients with lesions that were treated with SBRT or cEBRT and whose pain scores were evaluated 3 months after radiotherapy were included in this study. Pain response was evaluated according to the International Consensus Criteria. (3) Results: A total of 234 lesions (SBRT, n = 129; cEBRT, n = 105) were identified in our institutional database. To reduce the confounding effects, 162 patients were selected using a propensity score-matched analysis (n = 81 for each treatment). The OR rate at 3 months after SBRT was significantly higher than that after cEBRT (76.5% vs. 56.8%; p = 0.012). A noteworthy finding of our study is that the same trend was observed even after 6 months (75.9% vs. 50.0%; p = 0.011). The 1-year local failure rates after SBRT and cEBRT were 10.2% and 33.3% (p < 0.001), respectively. (4) Conclusions: Our findings suggest that SBRT is superior to cEBRT for pain palliation in patients with non-spine bone metastases.
ADC Values of Cytologically Benign and Cytologically Malignant 18 F-FDG PET-Positive Lymph Nodes of Head and Neck Squamous Cell Carcinoma
Authors: de Koekkoek-Doll Petra K. , Roberti Sander , Smit Laura , Vogel Wouter V. , Beets-Tan Regina , van den Brekel Michiel W. , Castelijns Jonas
Published: August 2022

Nodal staging (N-staging) in head and neck squamous cell carcinoma (HNSCC) is essential for treatment planning and prognosis. 18F-fluordeoxyglucose positron emission tomography (FDG-PET) has high performance for N-staging, although the distinction between cytologically malignant and reactive PET-positive nodes, and consequently, the selection of nodes for ultrasound-guided fine needle aspiration cytology (USgFNAC), is challenging. Diffusion-weighted magnetic resonance imaging (DW-MRI) can help to detect nodal metastases. We aim to investigate the potential of the apparent diffusion coefficient (ADC) as a metric to distinguish between cytologically reactive and malignant PET-positive nodes in order to improve node selection criteria for USgFNAC. PET-CT, real-time image-fused USgFNAC and DW-MRI to calculate ADC were available for 78 patients offered for routine N-staging. For 167 FDG-positive nodes, differences in the ADC between cytologically benign and malignant PET-positive nodes were evaluated, and both were compared to the ADC values of PET-negative reference nodes. Analyses were also performed in subsets of nodes regarding HPV status. A mild negative correlation between SUVmax and ADC was found. No significant differences in ADC values were observed between cytologically malignant and benign PET-positive nodes overall. Within the subset of non-HPV-related nodes, ADCb0-200-1000 was significantly lower in cytologically malignant PET-positive nodes when compared to benign PET-positive nodes. ADCb0-1000 and ADCb0-200-1000 were significantly lower (p = 0.018, 0.016, resp.) in PET-negative reference nodes than in PET-positive nodes. ADC was significantly higher in PET-negative reference nodes than in PET-positive nodes. The non-HPV-related subgroup showed significantly (p = 0.03) lower ADC values in cytologically malignant than in cytologically benign PET-positive nodes, which should help inform the node selection procedure for puncture.
Next Steps for Immunotherapy in Glioblastoma
Authors: Cao Toni Q. , Wainwright Derek A. , Lee-Chang Catalina , Miska Jason , Sonabend Adam M. , Heimberger Amy B. , Lukas Rimas V.
Published: August 2022

Outcomes for glioblastoma (GBM) patients undergoing standard of care treatment remain poor. Here we discuss the portfolio of previously investigated immunotherapies for glioblastoma, including vaccine therapy and checkpoint inhibitors, as well as novel emerging therapeutic approaches. In addition, we explore the factors that potentially influence response to immunotherapy, which should be considered in future research aimed at improving immunotherapy efficacy.
Theranostic Applications of an Ultra-Sensitive T1 and T2 Magnetic Resonance Contrast Agent Based on Cobalt Ferrite Spinel Nanoparticles
Authors: Mikhaylov Georgy , Mikac Urska , Butinar Miha , Turk Vito , Turk Boris , Psakhie Sergey , Vasiljeva Olga
Published: August 2022

Nano-dimensional materials have become a focus of multiple clinical applications due to their unique physicochemical properties. Magnetic nanoparticles represent an important class of nanomaterials that are widely studied for use as magnetic resonance (MR) contrast and drug delivery agents, especially as they can be detected and manipulated remotely. Using magnetic cobalt ferrite spinel (MCFS) nanoparticles, this study was aimed at developing a multifunctional drug delivery platform with MRI capability for use in cancer treatment. We found that MCFS nanoparticles demonstrated outstanding properties for contrast MRI (r1 = 22.1 s–1mM–1 and r2 = 499 s–1mM–1) that enabled high-resolution T1- and T2-weighted MRI-based signal detection. Furthermore, MCFS nanoparticles were used for the development of a multifunctional targeted drug delivery platform for cancer treatment that is concurrently empowered with the MR contrast properties. Their therapeutic effect in systemic chemotherapy and unique MRI double-contrast properties were confirmed in vivo using a breast cancer mouse tumor model. Our study thus provides an empirical basis for the development of a novel multimodal composite drug delivery system for anticancer therapy combined with noninvasive MRI capability.