bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutritional Enhancement of Health Beneficial Omega-3 Long-Chain Polyunsaturated Fatty Acids in the Muscle, Liver, Kidney, and Heart of Tattykeel Australian White MARGRA Lambs Fed Pellets Fortified with Omega-3 Oil in a Feedlot System
Authors: Pewan Shedrach Benjamin , Otto John Roger , Kinobe Robert Tumwesigye , Adegboye Oyelola Abdulwasiu , Malau-Aduli Aduli Enoch Othniel
Published: September 2021

The aim of this research was to evaluate the nutritional enhancement of omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) composition of edible lamb Longissimus thoracis et lumborum muscle, heart, kidney, and liver in response to dietary supplementation of lot-fed lambs with or without omega-3 oil fortified pellets. The hypothesis tested was that fortifying feedlot pellets with omega-3 oil will enhance the human health beneficial n-3 LC-PUFA composition of edible lamb muscle tissue and organs. Seventy-five Tattykeel Australian White lambs exclusive to the MARGRA brand, with an average body weight of 30 kg at six months of age, were randomly assigned to the following three dietary treatments of 25 lambs each, and lot-fed as a cohort for 47 days in a completely randomized experimental design: (1) Control grain pellets without oil plus hay; (2) Omega-3 oil fortified grain pellets plus hay; and (3) Commercial whole grain pellets plus hay. All lambs had ad libitum access to the basal hay diet and water. Post-slaughter fatty acid composition of the Longissimus thoracis et lumborum muscle, liver, kidney, and heart were determined using thee gas chromatography–mass spectrophotometry technique. Results indicated significant variations (p < 0.05) in fatty acid profiles between tissues and organs. Omega-3 oil fortified pellets significantly (p < 0.05) increased ≥C20 n-3 LC-PUFA (C20:5n-3 eicosapentaenoate, EPA + C22:5n3 docosapentaenoate, DPA + C22:6n3 docosahexanoate DHA); C18:3n-3 alpha-linolenate, ALA; C18:2 conjugated linoleic acid, CLA; total monounsaturated fatty acids, MUFA; polyunsaturated fatty acids, PUFA contents; and reduced the ratio of omega-6 to omega-3 fatty acids in all lamb organs and tissues without impacting shelf-life. The findings demonstrate that the inclusion of omega-3 oil in feedlot diets of lambs enhances the human health beneficial omega-3 long-chain polyunsaturated fatty acid profiles of edible muscle tissue and organs without compromising meat quality.
Actin Cytoskeleton Dynamics and Type I IFN-Mediated Immune Response: A Dangerous Liaison in Cancer?
Authors: Trono Paola , Tocci Annalisa , Musella Martina , Sistigu Antonella , Nisticò Paola
Published: September 2021

Chronic viral infection and cancer are closely inter-related and are both characterized by profound alteration of tissue homeostasis. The actin cytoskeleton dynamics highly participate in tissue homeostasis and act as a sensor leading to an immune-mediated anti-cancer and anti-viral response. Herein we highlight the crucial role of actin cytoskeleton dynamics in participating in a viral mimicry activation with profound effect in anti-tumor immune response. This still poorly explored field understands the cytoskeleton dynamics as a platform of complex signaling pathways which may regulate Type I IFN response in cancer. This emerging network needs to be elucidated to identify more effective anti-cancer strategies and to further advance the immuno-oncology field which has revolutionized the cancer treatment. For a progress to occur in this exciting arena we have to shed light on actin cytoskeleton related pathways and immune response. Herein we summarize the major findings, considering the double sword of the immune response and in particular the role of Type I IFN pathways in resistance to anti-cancer treatment.
Numerical Optimization of an Open-Ended Coaxial Slot Applicator for the Detection and Microwave Ablation of Tumors
Authors: Hessinger Carolin , Schüßler Martin , Klos Sabrina , Kochanek Markus , Jakoby Rolf
Published: September 2021

A multiobjective optimization method for a dual-mode microwave applicator is proposed. Dual-modality means that microwaves are used apart from the treatment, and also for the monitoring of the microwave ablation intervention. (1) The use of computational models to develop and improve microwave ablation applicator geometries is essential for further advances in this field. (2) Numerical electromagnetic–thermal coupled simulation models are used to analyze the performance of the dual-mode applicator in liver tissue; the sensitivity evaluation of the dual-mode applicator’s sensing mode constrains the set of optimal solutions. (3) Three Pareto-optimal design parameter sets are derived that are optimal in terms of applicator efficiency as well as volume and sphericity of the ablation zone. The resulting designs of the dual-mode applicator provide a suitable sensitivity to distinguish between healthy and tumorous liver tissue. (4) The optimized designs are presented and numerically characterized. An improvement on the performance of previously proposed dual-mode applicator designs is achieved. The multiphysical simulation model of electromagnetic and thermal properties of the applicator is applicable for future comprehensive design procedures.
Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity
Authors: van Haren Matthijs J. , Gao Yongzhi , Buijs Ned , Campagna Roberto , Sartini Davide , Emanuelli Monica , Mateuszuk Lukasz , Kij Agnieszka , Chlopicki Stefan , Escudé Martinez de Castilla Pol , Schiffelers Raymond , Martin Nathaniel I.
Published: September 2021

A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.
Convenient Genetic Encoding of Phenylalanine Derivatives through Their α-Keto Acid Precursors
Authors: Liu Li , Wang Bohao , Li Sheng , Xu Fengyuan , He Qi , Pan Chun , Gao Xiangdong , Yao Wenbing , Song Xiaoda
Published: September 2021

The activity and function of proteins can be improved by incorporation of non-canonical amino acids (ncAAs). To avoid the tedious synthesis of a large number of chiral phenylalanine derivatives, we synthesized the corresponding phenylpyruvic acid precursors. Escherichia coli strain DH10B and strain C321.ΔA.expΔPBAD were selected as hosts for phenylpyruvic acid bioconversion and genetic code expansion using the MmPylRS/pyltRNACUA system. The concentrations of keto acids, PLP and amino donors were optimized in the process. Eight keto acids that can be biotransformed and their coupled genetic code expansions were identified. Finally, the genetic encoded ncAAs were tested for incorporation into fluorescent proteins with keto acids.
TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain
Authors: Schlecht Anja , Vallon Mario , Wagner Nicole , Ergün Süleyman , Braunger Barbara M.
Published: September 2021

Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.
Beyond the GFAP-Astrocyte Protein Markers in the Brain
Authors: Jurga Agnieszka M. , Paleczna Martyna , Kadluczka Justyna , Kuter Katarzyna Z.
Published: September 2021

The idea of central nervous system as one-man band favoring neurons is long gone. Now we all are aware that neurons and neuroglia are team players and constant communication between those various cell types is essential to maintain functional efficiency and a quick response to danger. Here, we summarize and discuss known and new markers of astroglial multiple functions, their natural heterogeneity, cellular interactions, aging and disease-induced dysfunctions. This review is focused on newly reported facts regarding astrocytes, which are beyond the old stereotypes. We present an up-to-date list of marker proteins used to identify a broad spectrum of astroglial phenotypes related to the various physiological and pathological nervous system conditions. The aim of this review is to help choose markers that are well-tailored for specific needs of further experimental studies, precisely recognizing differential glial phenotypes, or for diagnostic purposes. We hope it will help to categorize the functional and structural diversity of the astroglial population and ease a clear readout of future experimental results.
Inhibition of Aminoglycoside 6′-N-acetyltransferase Type Ib (AAC(6′)-Ib): Structure–Activity Relationship of Substituted Pyrrolidine Pentamine Derivatives as Inhibitors
Authors: Rocha Kenneth , Magallon Jesus , Reeves Craig , Phan Kimberly , Vu Peter , Oakley-Havens Crista L. , Kwan Stella , Ramirez Maria Soledad , LaVoi Travis , Donow Haley , Chapagain Prem , Santos Radleigh , Pinilla Clemencia , Giulianotti Marc A. , Tolmasky Marcelo E.
Published: September 2021

The aminoglycoside 6′-N-acetyltransferase type Ib (AAC(6′)-Ib) is a common cause of resistance to amikacin and other aminoglycosides in Gram-negatives. Utilization of mixture-based combinatorial libraries and application of the positional scanning strategy identified an inhibitor of AAC(6′)-Ib. This inhibitor’s chemical structure consists of a pyrrolidine pentamine scaffold substituted at four locations (R1, R3, R4, and R5). The substituents are two S-phenyl groups (R1 and R4), an S-hydroxymethyl group (R3), and a 3-phenylbutyl group (R5). Another location, R2, does not have a substitution, but it is named because its stereochemistry was modified in some compounds utilized in this study. Structure–activity relationship (SAR) analysis using derivatives with different functionalities, modified stereochemistry, and truncations was carried out by assessing the effect of the addition of each compound at 8 µM to 16 µg/mL amikacin-containing media and performing checkerboard assays varying the concentrations of the inhibitor analogs and the antibiotic. The results show that: (1) the aromatic functionalities at R1 and R4 are essential, but the stereochemistry is essential only at R4; (2) the stereochemical conformation at R2 is critical; (3) the hydroxyl moiety at R3 as well as stereoconformation are required for full inhibitory activity; (4) the phenyl functionality at R5 is not essential and can be replaced by aliphatic groups; (5) the location of the phenyl group on the butyl carbon chain at R5 is not essential; (6) the length of the aliphatic chain at R5 is not critical; and (7) all truncations of the scaffold resulted in inactive compounds. Molecular docking revealed that all compounds preferentially bind to the kanamycin C binding cavity, and binding affinity correlates with the experimental data for most of the compounds evaluated. The SAR results in this study will serve as the basis for the design of new analogs in an effort to improve their ability to induce phenotypic conversion to susceptibility in amikacin-resistant pathogens.
Macrophages and Foam Cells: Brief Overview of Their Role, Linkage, and Targeting Potential in Atherosclerosis
Authors: Poznyak Anastasia V. , Nikiforov Nikita G. , Starodubova Antonina V. , Popkova Tatyana V. , Orekhov Alexander N.
Published: September 2021

Atherosclerosis is still one of the main causes of death around the globe. This condition leads to various life-threatening cardiovascular complications. However, no effective preventive measures are known apart from lifestyle corrections, and no cure has been developed. Despite numerous studies in the field of atherogenesis, there are still huge gaps in already poor understanding of mechanisms that underlie the disease. Inflammation and lipid metabolism violations are undoubtedly the key players, but many other factors, such as oxidative stress, endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. This overview is focusing on the role of macrophages in atherogenesis, which are at the same time a part of the inflammatory response, and also tightly linked to the foam cell formation, thus taking part in both crucial for atherogenesis processes. Being essentially involved in atherosclerosis development, macrophages and foam cells have attracted attention as a promising target for therapeutic approaches.
Cancer Stem Cells and Somatic Stem Cells as Potential New Drug Targets, Prognosis Markers, and Therapy Efficacy Predictors in Breast Cancer Treatment
Authors: Pershina Olga , Ermakova Natalia , Pakhomova Angelina , Widera Darius , Pan Edgar , Zhukova Mariia , Slonimskaya Elena , Morozov Sergey G. , Kubatiev Aslan , Dygai Alexander , Skurikhin Evgenii G.
Published: September 2021

New drug targets, markers of disease prognosis, and more efficient treatment options are an unmet clinical need in breast cancer (BC). We have conducted a pilot study including patients with luminal B stage breast cancer IIA–IIIB. The presence and frequency of various populations of cancer stem cells (CSC) and somatic stem cells were assessed in the blood, breast tumor tissue, and normal breast tissue. Our results suggest that patients with BC can be divided into two distinct groups based on the frequency of aldehyde dehydrogenase positive cells (ALDH1+ cells) in the blood (ALDH1hi and ALDH1low). In the ALDH1hi cells group, the tumor is dominated by epithelial tumor cells CD44+CD24low, CD326+CD44+CD24−, and CD326−CD49f+, while in the ALDH1low cells group, CSCs of mesenchymal origin and epithelial tumor cells (CD227+CD44+CD24− and CD44+CD24−CD49f+) are predominant. In vitro CSCs of the ALDH1low cells group expressing CD326 showed high resistance to cytostatics, CD227+ CSCs of the ALDH1hi cells group are sensitive to cytostatics. Epithelial precursors of a healthy mammary gland were revealed in normal breast tissue of patients with BC from both groups. The cells were associated with a positive effect of chemotherapy and remission in BC patients. Thus, dynamic control of their presence in blood and assessment of the sensitivity of CSCs to cytostatics in vitro can improve the effectiveness of chemotherapy in BC.
Faces of Pain during Dental Procedures: Reliability of Scoring Facial Expressions in Print Art
Authors: Lobbezoo Frank , Lam Xuan Mai , de la Mar Savannah , van de Rijt Liza J. M. , Kunz Miriam , van Selms Maurits K. A.
Published: September 2021

Background: Observational tools have been developed to assess pain in cognitively impaired individuals. It is not known, however, whether these tools are universal enough so that even pain depicted in print art can be assessed reliably. Therefore, the aim of this study was to assess the reliability in scoring facial expressions of pain in dental print art from the 17th, 18th, and 19th century, using a Short Form of the 15-item Pain Assessment in Impaired Cognition (PAIC15-SF) tool. Methods: Seventeen prints of patients undergoing dental procedures were scored twice by two inexperienced observers and an expert and once by a Gold Standard observer. Results: All observers achieved high intra-observer reliability for all four items of the category “facial expressions” and for three items of the category “body movements” (ICC: 0.748–0.991). The remaining two items of the category “body movements”, viz., “rubbing” and “restlessness”, were excluded from further research because it was not possible to calculate a reliable ICC. Overall, the intra-observer reliability of the expert was higher than that of the inexperienced observers. The inter-observer reliability scores varied from poor to excellent (ICC: 0.000–0.970). In comparison to the Gold Standard, the inter-observer reliability of the expert was higher than that of the inexperienced observers. Conclusion: The PAIC15-SF tool is universal enough even to allow reliable assessment of facial expressions of pain depicted in dental print art.
Mild Cognitive Impairment in Chronic Brain Injury Associated with Serum Anti-AP3B2 Autoantibodies: Report and Literature Review
Authors: Hansen Niels , Fitzner Dirk , Stöcker Winfried , Wiltfang Jens , Bartels Claudia
Published: September 2021

Background: Chronic traumatic brain injury is a condition that predisposes the brain to activate B-cells and produce neural autoantibodies. Anti-adaptor protein 3, subunit B2 (AP3B2) autoantibodies have thus far been associated with diseases affecting the cerebellum or vestibulocerebellum. Through this case report, we aim to broaden the spectrum of anti-AP3B2-associated disease. Case description: We report on a 51-year-old woman with a brain injury approximately 28 years ago who recently underwent neuropsychological testing, magnetic resonance imaging of the brain (cMRI), and cerebrospinal fluid (CSF) analysis. Neural autoantibodies were determined in serum and CSF. Our patient suffered from mild cognitive impairment (amnestic MCI, multiple domains) with stable memory deficits and a decline in verbal fluency and processing speed within a two-year interval after the first presentation in our memory clinic. Brain MRI showed brain damage in the right temporoparietal, frontolateral region and thalamus, as well as in the left posterior border of the capsula interna and white matter in the frontal region. Since the brain damage, she suffered paresis of the upper extremities on the left side and lower extremities on the right side as well as gait disturbance. Our search for autoantibodies revealed anti-AP3B2 autoantibodies in serum. Conclusions: Our report expands the spectrum of symptoms to mild cognitive impairment in addition to a gait disturbance associated with anti-AP3B2 autoantibodies. Furthermore, it is conceivable that a prior traumatic brain injury could initiate the development of anti-AP3B2-antibody-associated brain autoimmunity, reported here for the first time.
The Effect of Cannabis-Based Medicine on Neuropathic Pain and Spasticity in Patients with Multiple Sclerosis and Spinal Cord Injury: Study Protocol of a National Multicenter Double-Blinded, Placebo-Controlled Trial
Authors: Hansen Julie Schjødtz , Hansen Rikke Middelhede , Petersen Thor , Gustavsen Stefan , Oturai Annette Bang , Sellebjerg Finn , Sædder Eva Aggerholm , Kasch Helge , Rasmussen Peter Vestergaard , Finnerup Nanna Brix , Svendsen Kristina Bacher
Published: September 2021

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.
Role of Artificial Intelligence in the Early Diagnosis of Oral Cancer. A Scoping Review
Authors: García-Pola María , Pons-Fuster Eduardo , Suárez-Fernández Carlota , Seoane-Romero Juan , Romero-Méndez Amparo , López-Jornet Pia
Published: September 2021

The early diagnosis of cancer can facilitate subsequent clinical patient management. Artificial intelligence (AI) has been found to be promising for improving the diagnostic process. The aim of the present study is to increase the evidence on the application of AI to the early diagnosis of oral cancer through a scoping review. A search was performed in the PubMed, Web of Science, Embase and Google Scholar databases during the period from January 2000 to December 2020, referring to the early non-invasive diagnosis of oral cancer based on AI applied to screening. Only accessible full-text articles were considered. Thirty-six studies were included on the early detection of oral cancer based on images (photographs (optical imaging and enhancement technology) and cytology) with the application of AI models. These studies were characterized by their heterogeneous nature. Each publication involved a different algorithm with potential training data bias and few comparative data for AI interpretation. Artificial intelligence may play an important role in precisely predicting the development of oral cancer, though several methodological issues need to be addressed in parallel to the advances in AI techniques, in order to allow large-scale transfer of the latter to population-based detection protocols.
Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11
Authors: Jo Ukhyun , Murai Yasuhisa , Takebe Naoko , Thomas Anish , Pommier Yves
Published: September 2021

Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.
Extracellular Vesicles in Lung Cancer: Prospects for Diagnostic and Therapeutic Applications
Authors: Kato Taketo , Vykoukal Jody V. , Fahrmann Johannes F. , Hanash Samir
Published: September 2021

Extracellular vesicles (EVs) are nano-sized lipid-bound particles containing proteins, nucleic acids and metabolites released by cells. They have been identified in body fluids including blood, saliva, sputum and pleural effusions. In tumors, EVs derived from cancer and immune cells mediate intercellular communication and exchange, and can affect immunomodulatory functions. In the context of lung cancer, emerging evidence implicates EV involvement during various stages of tumor development and progression, including angiogenesis, epithelial to mesenchymal transformation, immune system suppression, metastasis and drug resistance. Additionally, tumor-derived EVs (TDEs) have potential as a liquid biopsy source and as a means of therapeutic targeting, and there is considerable interest in developing clinical applications for EVs in these contexts. In this review, we consider the biogenesis, components, biological functions and isolation methods of EVs, and the implications for their clinical utility for diagnostic and therapeutic applications in lung cancer.
Additional Value of Patient-Reported Symptom Monitoring in Cancer Care: A Systematic Review of the Literature
Authors: Lizán Luís , Pérez-Carbonell Lucía , Comellas Marta
Published: September 2021

Background: To describe the benefit of patient-reported symptom monitoring on clinical, other patient-reported, and economic outcomes. Methods: We conducted a systematic literature review using Medline/PubMed, limited to original articles published between 2011 and 2021 in English and Spanish, and focused on the benefit of patient-reported symptom monitoring on cancer patients. Results: We identified 16 reports that deal with the benefit of patient-reported symptom monitoring (collected mostly electronically) on different outcomes. Five studies showed that patient-reported symptom surveillance led to significantly improved survival compared with usual care—mainly through better symptom control, early detection of tumor recurrence, and extended chemotherapy use. Additionally, three evaluations demonstrated an improvement in Health-Related Quality of Life (HRQoL) associated with this monitoring strategy, specifically by reducing symptom severity. Additionally, six studies observed that this monitoring approach prevented unplanned emergency room visits and hospital readmissions, leading to a substantial decrease in healthcare usage. Conclusions: There is consistent evidence across the studies that patient-reported symptom monitoring might entail a substantial survival benefit for cancer patients, better HRQoL, and a considerable decrease in healthcare usage. Nonetheless, more studies should be conducted to demonstrate their effectiveness in addition to their cost-effectiveness in clinical practice.
Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade
Authors: Kanda Yasuhiro , Okazaki Taku , Katakai Tomoya
Published: September 2021

The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.
Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells
Authors: Chirshev Evgeny , Suzuki Tise , Wang Hanmin , Nguyen Anthony , Hojo Nozomi , Sanderman Linda , Mirshahidi Saied , Ioffe Yevgeniya J. , Unternaehrer Juli J.
Published: September 2021

High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.
External Basic Hyperthermia Devices for Preclinical Studies in Small Animals
Authors: Priester Marjolein I. , Curto Sergio , van Rhoon Gerard C. , ten Hagen Timo L. M.
Published: September 2021

Preclinical studies have shown that application of mild hyperthermia (40–43 °C) is a promising adjuvant to solid tumor treatment. To improve preclinical testing, enhance reproducibility, and allow comparison of the obtained results, it is crucial to have standardization of the available methods. Reproducibility of methods in and between research groups on the same techniques is crucial to have a better prediction of the clinical outcome and to improve new treatment strategies (for instance with heat-sensitive nanoparticles). Here we provide a preclinically oriented review on the use and applicability of basic hyperthermia systems available for solid tumor thermal treatment in small animals. The complexity of these techniques ranges from a simple, low-cost water bath approach, irradiation with light or lasers, to advanced ultrasound and capacitive heating devices.
A Novel Machine Learning Model to Predict the Photo-Degradation Performance of Different Photocatalysts on a Variety of Water Contaminants
Authors: Jiang Zhuoying , Hu Jiajie , Tong Matthew , Samia Anna C. , Zhang Huichun (Judy) , Yu Xiong (Bill)
Published: September 2021

This paper describes an innovative machine learning (ML) model to predict the performance of different metal oxide photocatalysts on a wide range of contaminants. The molecular structures of metal oxide photocatalysts are encoded with a crystal graph convolution neural network (CGCNN). The structure of organic compounds is encoded via digital molecular fingerprints (MF). The encoded features of the photocatalysts and contaminants are input to an artificial neural network (ANN), named as CGCNN-MF-ANN model. The CGCNN-MF-ANN model has achieved a very good prediction of the photocatalytic degradation rate constants by different photocatalysts over a wide range of organic contaminants. The effects of the data training strategy on the ML model performance are compared. The effects of different factors on photocatalytic degradation performance are further evaluated by feature importance analyses. Examples are illustrated on the use of this novel ML model for optimal photocatalyst selection and for assessing other types of photocatalysts for different environmental applications.
The Roles of the Let-7 Family of MicroRNAs in the Regulation of Cancer Stemness
Authors: Ma Yuxi , Shen Na , Wicha Max S. , Luo Ming
Published: September 2021

Cancer has long been viewed as a disease of normal development gone awry. Cancer stem-like cells (CSCs), also termed as tumor-initiating cells (TICs), are increasingly recognized as a critical tumor cell population that drives not only tumorigenesis but also cancer progression, treatment resistance and metastatic relapse. The let-7 family of microRNAs (miRNAs), first identified in C. elegans but functionally conserved from worms to human, constitutes an important class of regulators for diverse cellular functions ranging from cell proliferation, differentiation and pluripotency to cancer development and progression. Here, we review the current state of knowledge regarding the roles of let-7 miRNAs in regulating cancer stemness. We outline several key RNA-binding proteins, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) involved in the regulation of let-7 biogenesis, maturation and function. We then highlight key gene targets and signaling pathways that are regulated or mutually regulated by the let-7 family of miRNAs to modulate CSC characteristics in various types of cancer. We also summarize the existing evidence indicating distinct metabolic pathways regulated by the let-7 miRNAs to impact CSC self-renewal, differentiation and treatment resistance. Lastly, we review current preclinical studies and discuss the clinical implications for developing let-7-based replacement strategies as potential cancer therapeutics that can be delivered through different platforms to target CSCs and reduce/overcome treatment resistance when applied alone or in combination with current chemo/radiation or molecularly targeted therapies. By specifically targeting CSCs, these strategies have the potential to significantly improve the efficacy of cancer therapies.
PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model
Authors: Lee Minju , Kim Gee-Hye , Kim Miyeon , Seo Ji Min , Kim Yu Mi , Seon Mi Ra , Um Soyoun , Choi Soo Jin , Oh Wonil , Song Bo Ram , Jin Hye Jin
Published: September 2021

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.
Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor
Authors: Garcia Gonçalo , Pinto Sara , Cunha Mar , Fernandes Adelaide , Koistinaho Jari , Brites Dora
Published: September 2021

Neuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer’s disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124’s role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.
Co-Expression Network Analysis of MicroRNAs and Proteins in Severe Traumatic Brain Injury: A Systematic Review
Authors: Osgood Claire , Ahmed Zubair , Di Pietro Valentina
Published: September 2021

Traumatic brain injury (TBI) represents one of the leading causes of mortality and morbidity worldwide, placing an enormous socioeconomic burden on healthcare services and communities around the world. Survivors of TBI can experience complications ranging from temporary neurological and psychosocial problems to long-term, severe disability and neurodegenerative disease. The current lack of therapeutic agents able to mitigate the effects of secondary brain injury highlights the urgent need for novel target discovery. This study comprises two independent systematic reviews, investigating both microRNA (miRNA) and proteomic expression in rat models of severe TBI (sTBI). The results were combined to perform integrated miRNA-protein co-expression analyses with the aim of uncovering the potential roles of miRNAs in sTBI and to ultimately identify new targets for therapy. Thirty-four studies were included in total. Bioinformatic analysis was performed to identify any miRNA–protein associations. Endocytosis and TNF signalling pathways were highlighted as common pathways involving both miRNAs and proteins found to be differentially expressed in rat brain tissue following sTBI, suggesting efforts to find novel therapeutic targets that should be focused here. Further high-quality investigations are required to ascertain the involvement of these pathways and their miRNAs in the pathogenesis of TBI and other CNS diseases and to therefore uncover those targets with the greatest therapeutic potential.
Sustainable Agriculture through Multidisciplinary Seed Nanopriming: Prospects of Opportunities and Challenges
Authors: Shelar Amruta , Singh Ajay Vikram , Maharjan Romi Singh , Laux Peter , Luch Andreas , Gemmati Donato , Tisato Veronica , Singh Shubham Pratap , Santilli Maria Fernanda , Shelar Akanksha , Chaskar Manohar , Patil Rajendra
Published: September 2021

The global community decided in 2015 to improve people’s lives by 2030 by setting 17 global goals for sustainable development. The second goal of this community was to end hunger. Plant seeds are an essential input in agriculture; however, during their developmental stages, seeds can be negatively affected by environmental stresses, which can adversely affect seed vigor, seedling establishment, and crop production. Seeds resistant to high salinity, droughts and climate change can result in higher crop yield. The major findings suggested in this review refer nanopriming as an emerging seed technology towards sustainable food amid growing demand with the increasing world population. This novel growing technology could influence the crop yield and ensure the quality and safety of seeds, in a sustainable way. When nanoprimed seeds are germinated, they undergo a series of synergistic events as a result of enhanced metabolism: modulating biochemical signaling pathways, trigger hormone secretion, reduce reactive oxygen species leading to improved disease resistance. In addition to providing an overview of the challenges and limitations of seed nanopriming technology, this review also describes some of the emerging nano-seed priming methods for sustainable agriculture, and other technological developments using cold plasma technology and machine learning.
Preclinical Studies on the Effect of Rucaparib in Ovarian Cancer: Impact of BRCA2 Status
Authors: Saravi Sayeh , Alizzi Zena , Tosi Sabrina , Hall Marcia , Karteris Emmanouil
Published: September 2021

Background: Approximately 50% of ovarian cancer patients harbour homologous recombination repair deficiencies. These deficiencies have been successfully targeted using poly (ADP-ribose) polymerase inhibitors (PARPi) particularly for patients harbouring BRCA1/2 mutations. The aim of this study is to assess the effects of the PARPi rucaparib in vitro using cell lines with BRCA2 mutations in comparison to those with BRCA2 wild type. Methods: Cell proliferation assays, RT-qPCR, immunofluorescence, annexin V/PI assays were used to assess the effects of rucaparib in vitro. Results: The BRCA2 mutant ovarian cancer cell line PEO1 exhibited higher PARP1 activity when treated with H2O2 compared to wild type cell lines. The migratory and proliferative capacity of PEO1 cells was compromised following treatment with rucaparib 10 µM compared to BRCA2 wild-type cell lines via a mechanism involving the mTOR pathway. Rucaparib treatment significantly increased DNA damage primarily in PEO1 cells and SKOV3 cells compared with wild type. Conclusions: Appropriate identification of robust predictive biomarkers for homologous recombination deficiency using ‘liquid’ biopsies would facilitate the identification of patients suitable for PARPi therapy. Preliminary efforts to undertake such testing are described here. This study also demonstrates the mechanisms of action of rucaparib (PARPi) which may involve elements of the mTOR pathway.
A 3D Smoothed Particle Hydrodynamics Study of a Non-Symmetrical Rayleigh Collapse for an Empty Cavity
Authors: Albano Andrea , Alexiadis Alessio
Published: September 2021

In this work the first 3D Smoothed Particle Hydrodynamics model of a Rayleigh collapse for an empty cavity is proposed with the aim of improving the hydrodynamic analysis of a non-symmetrical collapse. The hydrodynamics of the model is validated against the solution of the Rayleigh-Plesset equation for a symmetrical collapse. The model is then used to simulate a non-symmetrical collapse of an empty cavity attached to a solid surface with γ=0.6 induced by an external pressure of 50 [MPa]. The results shows that is possible to identify three regions where the hydrodynamics of the collapsing cavity shows different features. For all the stages of the collapse the simulation shows smooth pressure and velocity fields in the liquid and in the solid phase with the formation of a vortex ring in the final phase of the collapse. Finally, the model is compared to a previous 2D model to highlight strong, weak points and the key differences of both approaches in final phase of the collapse.
Human Milk Oligosaccharides: A Comprehensive Review towards Metabolomics
Authors: Corona Laura , Lussu Anna , Bosco Alice , Pintus Roberta , Cesare Marincola Flaminia , Fanos Vassilios , Dessì Angelica
Published: September 2021

Human milk oligosaccharides (HMOs) are the third most represented component in breast milk. They serve not only as prebiotics but they exert a protective role against some significant neonatal pathologies such as necrotizing enterocolitis. Furthermore, they can program the immune system and consequently reduce allergies and autoimmune diseases’ incidence. HMOs also play a crucial role in brain development and in the gut barrier’s maturation. Moreover, the maternal genetic factors influencing different HMO patterns and their modulation by the interaction and the competition between active enzymes have been widely investigated in the literature, but there are few studies concerning the role of other factors such as maternal health, nutrition, and environmental influence. In this context, metabolomics, one of the newest “omics” sciences that provides a snapshot of the metabolites present in bio-fluids, such as breast milk, could be useful to investigate the HMO content in human milk. The authors performed a review, from 2012 to the beginning of 2021, concerning the application of metabolomics to investigate the HMOs, by using Pubmed, Researchgate and Scopus as source databases. Through this technology, it is possible to know in real-time whether a mother produces a specific oligosaccharide, keeping into consideration that there are other modifiable and unmodifiable factors that influence HMO production from a qualitative and a quantitative point of view. Although further studies are needed to provide clinical substantiation, in the future, thanks to metabolomics, this could be possible by using a dipstick and adding the eventual missing oligosaccharide to the breast milk or formula in order to give the best and the most personalized nutritional regimen for each newborn, adjusting to different necessities.