bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Novel Modalities Through Bibliometric Analysis for Timely Development of Regulatory Guidance: A Case Study of T Cell Immunity
Authors: Fukaya-Shiba Ai , Otsuka Kouhei , Sasaki Hajime , Shikano Mayumi , Wakao Rika
Published: October 2021

Background: The mission of medicines regulatory agencies is to ensure the timely access of innovative products for patients to improve public health. Thus, regulators should foresee evolving technologies and build expertise prior to reviewing innovative products. Novel modalities and new classes of therapeutics in biological or cell-based products represent a regulatory challenge because of knowledge gaps, as exemplified by the unexpected cytokine release syndrome in the first-in-human clinical trial of the CD28 super-agonist. Meanwhile, recent treatments harnessing T cell co-signaling pathways provide an opportunity for investigation. Therefore, this study aimed to systematically identify and evaluate novel modalities for T cell immunity to assess the need for regulatory guidance.

Methods: A PubMed search was carried out using the query, “immun* AND t lymph*” to select publications. Subsequently, a citation network was created, followed by clustering and text mining to identify the modalities and classes of therapeutics under development.

Results and Discussion: Analysis of the top 20 clusters revealed research domains characterized by keywords such as immune checkpoint antibody, chimeric antigen receptor (CAR)-T cells, microbiota, exosome, regulatory T cells, unconventional T cells, and vaccines. After reviewing the pharmacological concepts, clinical trial information, and available guidance, we presented a perspective on the future development of guidance for these domains.

Conclusion: Bibliometric analyses identified a set of innovative modalities targeted for drug development with which regulatory guidance is going to catch up. This strategy could help in the successful development of upcoming modalities to ensure readiness for clinical application as part of horizon scanning.
Topological Alterations of Working Memory Impairment in Aged Patients With Vascular Dementia
Authors: Zheng Cao , Zhang Rong-Sheng , Wan Ting , Zhao Jun-Sheng
Published: October 2021

Aneurysmal subarachnoid hemorrhage (aSAH) is a common disease causing vascular dementia. Survivors often suffer from cognitive impairment especially working memory deficit. Currently, lack of theoretical support limits the improvement of cognitive intervention or rehabilitation. It is unclear how the large-scale network differs and to what extent is the brain network affected? Our study aims to provide novel information about the topological characteristics of brain organization, especially “small-world” property. A total of 62 aSAH patients are enrolled in this study. They are divided into two groups according to the syndrome of working memory deficit. Their working memory function is evaluated by TMT-B and AVLT (Chinese version). Functional MRI scan is also performed for detecting resting-state cortical plasticity. We utilized ICA to extract functional sub-networks including working memory network from imaging data. And then we establish binarized network and calculate the small-worldness property as well as local and global efficiency of networks. aSAH group with working memory deficit shows no significant difference of clustering coefficient with control group. Our study discovered significant decrease of characteristic path length indicating an increase of overall routing efficiency. We reason that patients with working memory deficit have to recruit more neuronal resources and thus develops higher overall routing efficiency of local network. This study provides novel information about the neural alterations of aSAH patients with working memory deficit. It might contribute to the understanding of neural mechanism and the improvement of current intervention for vascular dementia.
User-Centered Design and Development of the Modular TWIN Lower Limb Exoskeleton
Authors: Laffranchi Matteo , D'Angella Stefano , Vassallo Christian , Piezzo Chiara , Canepa Michele , De Giuseppe Samuele , Di Salvo Mirco , Succi Antonio , Cappa Samuele , Cerruti Giulio , Scarpetta Silvia , Cavallaro Lorenzo , Boccardo Nicolò , D'Angelo Marialaura , Marchese Claudia , Saglia Jody A. , Guanziroli Eleonora , Barresi Giacinto , Semprini Marianna , Traverso Simone , Maludrottu Stefano , Molteni Franco , Sacchetti Rinaldo , Gruppioni Emanuele , De Michieli Lorenzo
Published: October 2021

For decades, powered exoskeletons have been considered for possible employment in rehabilitation and personal use. Yet, these devices are still far from addressing the needs of users. Here, we introduce TWIN, a novel modular lower limb exoskeleton for personal use of spinal-cord injury (SCI) subjects. This system was designed according to a set of user requirements (lightweight and autonomous portability, quick and autonomous donning and setup, stability when standing/walking, cost effectiveness, long battery life, comfort, safety) which emerged during participatory investigations that organically involved patients, engineers, designers, physiatrists, and physical therapists from two major rehabilitation centers in Italy. As a result of this user-centered process, TWIN's design is based on a variety of small mechatronic modules which are meant to be easily assembled and donned on or off by the user in full autonomy. This paper presents the development of TWIN, an exoskeleton for personal use of SCI users, and the application of user-centered design methods that are typically adopted in medical device industry, for its development. We can state that this approach revealed to be extremely effective and insightful to direct and continuously adapt design goals and activities toward the addressment of user needs, which led to the development of an exoskeleton with modular mechatronics and novel lateral quick release systems. Additionally, this work includes the preliminary assessment of this exoskeleton, which involved healthy volunteers and a complete SCI patient. Tests validated the mechatronics of TWIN and emphasized its high potential in terms of system usability for its intended use. These tests followed procedures defined in existing standards in usability engineering and were part of the formative evaluation of TWIN as a premise to the summative evaluation of its usability as medical device.
How Many Muscles? Optimal Muscles Set Search for Optimizing Myocontrol Performance
Authors: Camardella Cristian , Junata Melisa , Tse King Chun , Frisoli Antonio , Tong Raymond Kai-Yu
Published: October 2021

In myo-control, for computational and setup constraints, the measurement of a high number of muscles is not always possible: the choice of the muscle set to use in a myo-control strategy depends on the desired application scope and a search for a reduced muscle set, tailored to the application, has never been performed. The identification of such set would involve finding the minimum set of muscles whose difference in terms of intention detection performance is not statistically significant when compared to the original set. Also, given the intrinsic sensitivity of muscle synergies to variations of EMG signals matrix, the reduced set should not alter synergies that come from the initial input, since they provide physiological information on motor coordination. The advantages of such reduced set, in a rehabilitation context, would be the reduction of the inputs processing time, the reduction of the setup bulk and a higher sensitivity to synergy changes after training, which can eventually lead to modifications of the ongoing therapy. In this work, the existence of a minimum muscle set, called optimal set, for an upper-limb myoelectric application, that preserves performance of motor activity prediction and the physiological meaning of synergies, has been investigated. Analyzing isometric contractions during planar reaching tasks, two types of optimal muscle sets were examined: a subject-specific one and a global one. The former relies on the subject-specific movement strategy, the latter is composed by the most recurrent muscles among subjects specific optimal sets and shared by all the subjects. Results confirmed that the muscle set can be reduced to achieve comparable hand force estimation performances. Moreover, two types of muscle synergies namely “Pose-Shared” (extracted from a single multi-arm-poses dataset) and “Pose-Related” (clustering pose-specific synergies), extracted from the global optimal muscle set, have shown a significant similarity with full-set related ones meaning a high consistency of the motor primitives. Pearson correlation coefficients assessed the similarity of each synergy. The discovering of dominant muscles by means of the optimization of both muscle set size and force estimation error may reveal a clue on the link between synergistic patterns and the force task.
Emerging Evidence on the Effects of Dietary Factors on the Gut Microbiome in Colorectal Cancer
Authors: Appunni Sandeep , Rubens Muni , Ramamoorthy Venkataraghavan , Tonse Raees , Saxena Anshul , McGranaghan Peter , Kaiser Adeel , Kotecha Rupesh
Published: October 2021

Dietary factors have important role in modulating the gut microbiome, which in-turn regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome are decisive factors in colorectal cancer (CRC) tumorigenesis. Altered gut microbiome is associated with impaired immune response, and the release of carcinogenic or genotoxic substances which are the major microbiome-induced mechanisms implicated in CRC pathogenesis. Diets low in dietary fibers and phytomolecules as well as high in red meat are important dietary changes which predispose to CRC. Dietary fibers which reach the colon in an undigested form are further metabolized by the gut microbiome into enterocyte friendly metabolites such as short chain fatty acid (SCFA) which provide anti-inflammatory and anti-proliferative effects. Healthy microbiome supported by dietary fibers and phytomolecules could decrease cell proliferation by regulating the epigenetic events which activate proto-oncogenes and oncogenic pathways. Emerging evidence show that predominance of microbes such as Fusobacterium nucleatum can predispose the colonic mucosa to malignant transformation. Dietary and lifestyle modifications have been demonstrated to restrict the growth of potentially harmful opportunistic organisms. Synbiotics can protect the intestinal mucosa by improving immune response and decreasing the production of toxic metabolites, oxidative stress and cell proliferation. In this narrative review, we aim to update the emerging evidence on how diet could modulate the gut microbial composition and revive colonic epithelium. This review highlights the importance of healthy plant-based diet and related supplements in CRC prevention by improving the gut microbiome.
Involvement of Arabidopsis Multi-Copper Oxidase-Encoding LACCASE12 in Root-to-Shoot Iron Partitioning: A Novel Example of Copper-Iron Crosstalk
Authors: Bernal María , Krämer Ute
Published: October 2021

Numerous central biological processes depend on the participation of the essential elements iron (Fe) or copper (Cu), including photosynthesis, respiration, cell wall remodeling and oxidative stress protection. Yet, both Fe and Cu metal cations can become toxic when accumulated in excess. Because of the potent ligand-binding and redox chemistries of these metals, there is a need for the tight and combined homeostatic control of their uptake and distribution. Several known examples pinpoint an inter-dependence of Fe and Cu homeostasis in eukaryotes, mostly in green algae, yeast and mammals, but this is less well understood in multicellular plants to date. In Arabidopsis, Cu deficiency causes secondary Fe deficiency, and this is associated with reduced in vitro ferroxidase activity and decreased root-to-shoot Fe translocation. Here we summarize the current knowledge of the cross-talk between Cu and Fe homeostasis and present a partial characterization of LACCASE12 (LAC12) that encodes a member of the multicopper oxidase (MCO) protein family in Arabidopsis. LAC12 transcript levels increase under Fe deficiency. The phenotypic characterization of two mutants carrying T-DNA insertions suggests a role of LAC12 in root-to-shoot Fe partitioning and in maintaining growth on Fe-deficient substrates. A molecular understanding of the complex interactions between Fe and Cu will be important for combating Fe deficiency in crops and for advancing biofortification approaches.
Dose-Dependent Application of Straw-Derived Fulvic Acid on Yield and Quality of Tomato Plants Grown in a Greenhouse
Authors: Zhang Peijia , Zhang Hongjia , Wu Guoqing , Chen Xiaoyuan , Gruda Nazim , Li Xun , Dong Jinlong , Duan Zengqiang
Published: October 2021

Fulvic acids are organic compounds widely distributed in soils, and the application of fulvic acids is thought to increase crop yield and quality. However, the effects vary among various sources and doses of fulvic acids and environmental and growth conditions of crops. Here, we investigated the effects of bioresource-derived (corn straw) fulvic acids on plant production and quality of tomato plants and soil chemical properties in soil cultures while experiments on seed germination and hydroponics were conducted to explore the underlying mechanism. Base dressing with 2.7 g kg–1 increased the yield of tomato by 35.0% at most as increased fruit number. Fulvic acids increased the concentrations of minerals, such as Ca, Fe, and Zn and the concentrations of citric, malic, and some amino acids in berries of tomato but did not affect the concentrations of soluble sugars and aromatic substances in tomato fruits. Similarly, fulvic acids at 80–160 mg L–1 increased germination rate, growth vigor, and radicle elongation of tomato seeds while it increased plant biomass, concentrations of nutrients, and root length of tomato plants in hydroponics to the greatest extent in general. The increases in yield and quality can be attributed to the improvement in root growth and, thus, increased nutrient uptake. In addition, the base application of fulvic acids improved soil cation exchange capacity and soil organic matter to an extent. In conclusion, base dressing and the addition into solution of fulvic acids at moderate doses facilitate root growth and nutrient uptake and, thus, vegetable production and quality; therefore, fulvic acids can be an effective component for designing new biofertilizers for sustainable agricultural production.
A Receiver Perspective on Knowledge Sharing Impact on Consumer–Brand Relationship in Virtual Communities
Authors: Zhang Jiemei , Qi Shaojing , Lyu Bei
Published: October 2021

The virtual community offers groups of consumers a knowledge-shared platform, wherein shared brand information influences the brand cognition of others. Using stimulus–organism–response (SOR) model, this study constructs a research framework for the influence of knowledge sharing on consumer–brand relationship in virtual communities. The empirical analysis shows that knowledge-sharing quality has significant positive effects on the sense of virtual community, as does the sense of virtual community on the consumer–brand relationships. This study supports the strengthening of consumer–brand relationships and the enrichment of following research on knowledge sharing of the consumer in virtual communities. Thus, companies should encourage consumers to actively participate in brand activities and focus on the development of consumer–brand relationships during participation in brand promotion.
The Impact of Specialized Knowledge Search on Enterprise Innovation
Authors: Liu Xianyue , Yao Zhipeng , Liu Caixia , Zhao Dali , Lin Chunpei
Published: October 2021

Against the backdrop of the fierce competition in the market nowadays, a closed innovation model based on internal knowledge is no longer sufficient to support enterprises in search of high-performance innovation. Instead, corporations are desperately required to search for resources of external knowledge to meet their innovation goals. Existing studies on open innovation in corporate management failed to fully elaborate on the mechanism of how the external knowledge search could impose an impact on sustaining innovation and disruptive innovation. In this study, the external knowledge search was divided into three categories according to the knowledge-based theory, namely, the scientific knowledge search, the market knowledge search, and the supply-chain knowledge search. While taking into account the moderating role of the focus of attention of the manager, we analyzed the statistical results of 485 questionnaires collected from manufacturing enterprises to elaborate on the mechanism of how the specialized knowledge search could impose an impact on sustaining innovation and disruptive innovation. Our research conclusions are expected to enrich existing studies on the factors contributing to corporate innovation, including but not limited to sustaining innovation and disruptive innovation. In addition, the research findings are expected to lay an empirical foundation by summarizing previous theoretical opinions while providing references for subsequent in-depth studies in the meantime. Moreover, the paper has put forward practical management measures and suggestions that could enable enterprises in developing countries to search and effectively transform the external knowledge into innovative outcomes. Last but not least, this study is expected to provide both theoretical and practical guidance for enterprises to further facilitate innovation by means of knowledge search.
Clinical Effectiveness of Training for Awareness Resilience and Action Online Compared to Standard Treatment for Adolescents and Young Adults With Depression: Study Protocol and Analysis Plan for a Pragmatic, Multi-Center Randomized Controlled Superiority Trial
Authors: Ekbäck Erik , Granåsen Gabriel , Svärling Rachel , Blomqvist Ida , Henje Eva
Published: October 2021

Depression in adolescents and young adults is an increasing global health concern. Available treatments are not sufficiently effective and relapse rates remain high. The novel group-treatment program “Training for Awareness, Resilience and Action” (TARA) targets specific mechanisms based on neuroscientific findings in adolescent depression. TARA is framed within the National Institute of Mental Health's Research Domain Criteria and has documented feasibility and preliminary efficacy in the treatment of adolescent depression. Since neurodevelopment continues well into the mid-twenties, age-adapted treatments are warranted also for young adults. Patients 15–22 years old, with either major depressive disorder (MDD) or persistent depressive disorder (PDD) according to the DSM-IV/5 or a rating >40 on the clinician rating scale Children's Depression Rating Scale—Revised (CDRS-R), will be recruited from specialized Child and Adolescent Psychiatry and local Youth-Clinics and randomized to either TARA or standard treatment, including but not limited to antidepressant medication and/or psychotherapy. Outcome measures will be obtained before randomization (T0), after 3 months of treatment (T1) and at 6-months- (T2) and 24-months- (T3) follow-up. Additionally, dose-response measures will be obtained weekly in the TARA-arm and measures for mediation-analysis will be obtained halfway through treatment (T0.5). Primary outcome measure is Reynolds Adolescent Depression Scale (RADS-2) score at T1. Secondary outcome measures include RADS-2 score at T2, Multidimensional Anxiety Scale for Children at T1 and T2, and CDRS-R at T1. Additional outcome measures include self-report measures of depression-associated symptoms, systemic bio-indicators of depression from blood and hair, heartrate variability, brain magnetic resonance imaging, as well as three-axial accelerometry for sleep-objectivization. Qualitative data will be gathered to reach a more comprehensive understanding of the factors affecting adolescents and young adults with depression and the extent to which the different treatments address these factors. In summary, this article describes the design, methods and statistical analysis plan for pragmatically evaluating the clinical effectiveness of TARA. This will be the first RCT to examine the effects of TARA compared to standard treatment for adolescents and young adults with MDD or PDD. We argue that this study will extend the current knowledgebase regarding the treatment of depression.

NCT Registration: identifier [NCT04747340].
Examining Blood Vessels Using Sound Waves
Authors: Tallon Christine M. , Smith Kurt J. , Lewis Nia , McManus Ali M.
Published: October 2021

Your heart works as a team with your body’s blood vessels. Your heart pumps the blood, while blood vessels help the blood travel all over your body, just as a garden hose helps move water all around your garden. Blood carries oxygen and other nutrients to your muscles and organs and removes carbon dioxide and other wastes. These are very important chores for the blood! Sometimes doctors need to check whether the heart and blood vessels are working properly, or scientists may want to study how blood vessels work as people get older. To do this, a technique called ultrasound is used to take pictures and videos of the blood vessels and the blood moving through them. But how does sound create pictures? This article will explain how ultrasound works and how it can be used to examine blood vessels and the speed of the blood flow.
Bioengineering of Extracellular Vesicles: Exosome-Based Next-Generation Therapeutic Strategy in Cancer
Authors: Saha Priyanka , Datta Suchisnigdha , Ghosh Sukanya , Samanta Anurima , Ghosh Paramita , Sinha Dona
Published: October 2021

Extracellular nano vesicles and exosomes hold compelling evidence in intercellular communication. Exosomal intracellular signal transduction is mediated by the transfer of cargo proteins, lipids, micro (mi)RNAs, long noncoding (lnc)RNAs, small interfering (si)RNAs, DNA, and other functional molecules that play a pivotal role in regulating tumor growth and metastasis. However, emerging research trends indicate that exosomes may be used as a promising tool in anticancer treatment. This review features a majority of the bioengineering applications of fabricated exosomal cargoes. It also encompasses how the manipulation and delivery of specific cargoes—noncoding RNAs (ncRNAs), recombinant proteins, immune-modulators, chemotherapeutic drugs, and other small molecules—may serve as a precise therapeutic approach in cancer management.
Tyrosine Kinase Inhibitors Improved Survival of Critically Ill EGFR-Mutant Lung Cancer Patients Undergoing Mechanical Ventilation
Authors: Lee I-Hsien , Yang Ching-Yao , Shih Jin-Yuan , Yu Chong-Jen
Published: October 2021

Background: Respiratory failure requiring mechanical ventilation is the major reason for lung cancer patients being admitted to the intensive care unit (ICU). Though molecular targeted therapies, especially epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), have largely improved the survival of oncogene-driven lung cancer patients, few studies have focused on the performance of TKI in such settings. Materials and Methods: This was a retrospective cohort study enrolling non-small cell lung cancer (NSCLC) patients who harbored sensitizing EGFR mutation and had received EGFR-TKIs as first-line cancer therapy in the ICU with mechanical ventilator use. The primary outcome was the 28-day ICU survival rate, and secondary outcomes were the rate of successful weaning from the ventilator and overall survival. Results: A total of 35 patients were included. The 28-day ICU survival rate was 77%, and the median overall survival was 67 days. Multivariate logistic regression revealed that shock status was associated with a lower 28-day ICU survival rate independently (odds ratio (OR) 0.017, 95% confidence interval (CI), 0.000–0.629, p = 0.027), and that L858R mutation (L858R compared with exon 19 deletion, OR, 0.014, 95% CI 0.000–0.450, p = 0.016) and comorbidities of diabetes mellitus (DM) (OR, 0.032, 95% CI, 0.000–0.416, p = 0.014)) were independently predictive of weaning failure. The successful weaning rate was 43%, and the median of ventilator-dependent duration was 22 days (IQR, 12–29). Conclusions: For EGFR mutant lung cancer patients suffering from respiratory failure and undergoing mechanical ventilation, TKI may still be useful, especially in those with EGFR del19 mutation or without shock and DM comorbidity.
Relevant Biological Effects of Varicocele Embolization with N-Butyl Cyanoacrylate Glue on Semen Parameters in Infertile Men
Authors: Chevallier Olivier , Fauque Patricia , Poncelet Carole , Guillen Kévin , Comby Pierre-Olivier , Astruc Karine , Barberet Julie , Falvo Nicolas , Simon Emmanuel , Loffroy Romaric
Published: October 2021

Surgical treatment or varicocele embolization (VE) with sclerosing or mechanical embolic agents have been shown to improve the semen parameters of infertile men. The aim of this study was to evaluate the impact of VE using N-butyl cyanoacrylate (NBCA) glue on semen parameters in infertile men. From January 2014 to June 2018, infertile adult patients with stage 3 varicocele and an initial semen analysis showing at least one abnormal semen parameter, and who were successfully embolized with NBCA Glubran®2 glue, were retrospectively recruited. The availability of a second semen analysis after VE was mandatory for patient inclusion. The primary endpoint was the change in total sperm number (TSN) after VE. The other parameters of interest were progressive and total sperm motilities (Smot) at 1 h (H1), sperm vitality (SV) and morphology (SMor). One hundred and two patients were included. Eight patients presented null TSN before and after VE. Among the remaining 94 patients, a significant improvement in the median TSN after VE was shown (31.79 × 106/ejaculate [IQR: 11.10–127.40 × 106/ejaculate] versus 62.24 × 106/ejaculate [IQR: 17.90–201.60 × 106/ejaculate], p = 0.0295). Significant improvement in TSN was found for the 60 oligo- or azoospermic patients (p = 0.0007), whereas no significant change was found for the 42 patients with normal initial TSN (p = 0.49). Other parameters, such as progressive and total SMot, SV and SMor, also significantly improved after VE (p = 0.0003, 0.0013, 0.0356 and 0.007, respectively). The use of NBCA glue as an embolic agent for VE in infertile men with stage 3 varicocele significantly improves the semen parameters.
The Role of Uterine Natural Killer Cells on Recurrent Miscarriage and Recurrent Implantation Failure: From Pathophysiology to Treatment
Authors: Sfakianoudis Konstantinos , Rapani Anna , Grigoriadis Sokratis , Pantou Agni , Maziotis Evangelos , Kokkini Georgia , Tsirligkani Chrysanthi , Bolaris Stamatis , Nikolettos Konstantinos , Chronopoulou Margarita , Pantos Konstantinos , Simopoulou Mara
Published: October 2021

Uterine natural killer (uNK) cells constitute a unique uterine leucocyte subpopulation facilitating implantation and maintaining pregnancy. Herein, we critically analyze current evidence regarding the role of uNK cells in the events entailed in recurrent implantation failure (RIF) and recurrent miscarriages (RM). Data suggest an association between RIF and RM with abnormally elevated uNK cells’ numbers, as well as with a defective biological activity leading to cytotoxicity. However, other studies do not concur on these associations. Robust data suggesting a definitive causative relationship between uNK cells and RIF and RM is missing. Considering the possibility of uNK cells involvement on RIF and RM pathophysiology, possible treatments including glucocorticoids, intralipids, and intravenous immunoglobulin administration have been proposed towards addressing uNK related RIF and RM. When considering clinical routine practice, this study indicated that solid evidence is required to report on efficiency and safety of these treatments as there are recommendations that clearly advise against their employment. In conclusion, defining a causative relationship between uNK and RIF–RM pathologies certainly merits investigation. Future studies should serve as a prerequisite prior to proposing the use of uNK as a biomarker or prior to targeting uNK cells for therapeutic purposes addressing RIF and RM.
Phoenixin as a New Target in the Development of Strategies for Endometriosis Diagnosis and Treatment
Authors: Kulinska Karolina Iwona , Andrusiewicz Mirosław , Dera-Szymanowska Anna , Billert Maria , Skrzypski Marek , Szymanowski Krzysztof , Nowak-Markwitz Ewa , Kotwicka Małgorzata , Wołuń-Cholewa Maria
Published: October 2021

Small integral membrane protein 20/phoenixin (SMIM20/PNX) and its receptor GPR173 (G Protein-Coupled Receptor 173) play a role in the regulation of the hypothalamic–pituitary–gonadal axis (HPG). The aim of the study was to determine PNX, FSH, LH, and 17β-estradiol association in women with endometriosis, and the expression of SMIM20/PNX signaling via GPR173. Serum PNX, FSH, LH, and 17β-estradiol concentrations were measured by enzyme and electrochemiluminescence immunoassay. SMIM20/PNX and GPR173 expression in the eutopic and ectopic endometrium was assessed by qPCR and immunohistochemistry. Reduced PNX level, increased LH/FSH ratio and elevated 17β-estradiol concentration were found in patients with endometriosis. No differences in SMIM20 expression were observed between the studied endometria. GPR173 expression was lower in ectopic than in eutopic endometria. SMIM20 expression was mainly restricted to stroma. GPR173 was detected in some eutopic and ectopic stromal cells and in eutopic glandular epithelial cells. Discriminant analysis indicates the diagnostic relevance of PNX and LH/FSH ratio in patients with endometriosis. In women with endometriosis, reduced PNX levels and GPR173 expression may be responsible for HPG axis dysregulation. These new insights may contribute to a better understanding of the pathophysiology of endometriosis and provide the basis for a new strategy for diagnosis and treatment of endometriosis.
Lobeglitazone Exerts Anti-Inflammatory Effect in Lipopolysaccharide-Induced Bone-Marrow Derived Macrophages
Authors: Jeong Dabin , Ko Wan-Kyu , Kim Seong-Jun , Han Gong-Ho , Lee Daye , Sheen Seung-Hun , Sohn Seil
Published: October 2021

The purpose of this study is to elucidate the anti-inflammatory effect of lobeglitazone (LOBE) in lipopolysaccharide (LPS)-induced bone-marrow derived macrophages (BMDMs). We induced nitric oxide (NO) production and pro-inflammatory gene expression through LPS treatment in BMDMs. The changes of NO release and expression of pro-inflammatory mediators by LOBE were assessed via NO quantification assay and a real-time quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, the regulatory effect of LOBE on activation of mitogen-activated protein kinase (MAPK) signaling pathway was investigated by measuring the phosphorylation state of extracellular regulatory protein (ERK) and c-Jun N-terminal kinase (JNK) proteins by Western blot. Our results show that LOBE significantly reduced LPS-induced NO production and pro-inflammatory gene expression of interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and monocyte chemoattractant protein-1 (MCP-1). Moreover, LOBE reduced phosphorylation levels of ERK and JNK of MAPK signaling pathway. In conclusion, LOBE exerts an anti-inflammatory effect in LPS-induced BMDMs by suppression of NO production and pro-inflammatory gene expression, and this effect is potentially through inhibition of the MARK signaling pathway.
Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine
Authors: Carrasco-Hernández Laura , Quintana-Gallego Esther , Calero Carmen , Reinoso-Arija Rocío , Ruiz-Duque Borja , López-Campos José Luis
Published: October 2021

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.
A Systematic Review and Meta-Analysis of the Effect of Pentagalloyl Glucose Administration on Aortic Expansion in Animal Models
Authors: Golledge Jonathan , Thanigaimani Shivshankar , Phie James
Published: October 2021

Background: The aim of this systematic review was to pool evidence from studies testing if pentagalloyl glucose (PGG) limited aortic expansion in animal models of abdominal aortic aneurysm (AAA). Methods: The review was conducted according to the PRISMA guidelines and registered with PROSPERO. The primary outcome was aortic expansion assessed by direct measurement. Secondary outcomes included aortic expansion measured by ultrasound and aortic diameter at study completion. Sub analyses examined the effect of PGG delivery in specific forms (nanoparticles, periadventitial or intraluminal), and at different times (from the start of AAA induction or when AAA was established), and tested in different animals (pigs, rats and mice) and AAA models (calcium chloride, periadventitial, intraluminal elastase or angiotensin II). Meta-analyses were performed using Mantel-Haenszel’s methods with random effect models and reported as mean difference (MD) and 95% confidence intervals (CIs). Risk of bias was assessed with a customized tool. Results: Eleven studies reported in eight publications involving 214 animals were included. PGG significantly reduced aortic expansion measured by direct observation (MD: −66.35%; 95% CI: −108.44, −24.27; p = 0.002) but not ultrasound (MD: −32.91%; 95% CI: −75.16, 9.33; p = 0.127). PGG delivered intravenously within nanoparticles significantly reduced aortic expansion, measured by both direct observation (MD: −116.41%; 95% CI: −132.20, −100.62; p < 0.001) and ultrasound (MD: −98.40%; 95% CI: −113.99, −82.81; p < 0.001). In studies measuring aortic expansion by direct observation, PGG administered topically to the adventitia of the aorta (MD: −28.41%; 95% CI −46.57, −10.25; p = 0.002), studied in rats (MD: −56.61%; 95% CI: −101.76, −11.46; p = 0.014), within the calcium chloride model (MD: −56.61%; 95% CI: −101.76, −11.46; p = 0.014) and tested in established AAAs (MD: −90.36; 95% CI: −135.82, −44.89; p < 0.001), significantly reduced aortic expansion. The findings of other analyses were not significant. The risk of bias of all studies was high. Conclusion: There is inconsistent low-quality evidence that PGG inhibits aortic expansion in animal models.
Genetic Drivers of Ileal Neuroendocrine Tumors
Authors: Carpizo Darren R. , Harris Chris R.
Published: October 2021

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes.
Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine
Authors: Barry Evan R. , Simov Vladimir , Valtingojer Iris , Venier Olivier
Published: October 2021

The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.
Longitudinal Changes in Serum Creatinine Levels and Urinary Biomarkers in Late Preterm Infants during the First Postnatal Week: Association with Acute Kidney Injury and Treatment with Aminoglycoside
Authors: Lee Sang-Yoon , Moon Jung-Eun , Park Sook-Hyun
Published: October 2021

We aimed to determine the incidence of acute kidney injury (AKI) and longitudinal changes in SCr levels and urinary biomarkers associated with AKI and aminoglycoside (AG) medication during the first week of life of late preterm infants. Urine biomarkers and SCr were measured in thirty late preterm infants on days one, two, five, and seven postnatal. Urine biomarkers included neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), Tamm–Horsfall glycoprotein (THP), and liver fatty-acid-binding protein (L-FABP). Gestational age was positively correlated with SCr levels at birth, but inversely correlated with SCr levels at day five and day seven. Eighteen (60%) infants had stage 1 AKI, and twenty (67%) infants were treated with AGs. Infants with AKI had lower gestational age and lower birth weight than those without AKI. Urinary biomarkers adjusted according to uCr levels in infants with AKI were not statistically different from those in infants without AKI. There were no significant differences in incidence of AKI, and SCr levels during and after cessation of AG treatment. The uMCP-1/Cr ratio at days five and seven was higher in infants treated with AG than in non-treated infants.
Fluid Supply and Feeding Practices in Cooled Asphyxiated Newborns
Authors: Markus Mona , Giannakis Stamatios , Ruhfus Maria , Stein Anja , Heep Axel , Plagemann Thorsten , Jahn Peter , Hoehn Thomas , Felderhoff-Mueser Ursula , Sabir Hemmen
Published: October 2021

Therapeutic hypothermia (TH) for 72 h is the standard treatment to reduce neurological deficits in term newborns with hypoxic-ischemic encephalopathy. There is a large variability regarding nutritional supply during TH treatment in asphyxiated newborns. We performed a retrospective multicentre study in four level I (highest level of care in Germany) NICUs, including 135 asphyxiated term newborns undergoing TH. We analyzed enteral and parenteral nutritional supply during and after TH. We correlated nutritional supply with risk factors for encephalopathy, pH, Sarnat score, mechanical ventilation, seizures, and sedation. A total of 120 of 135 neonates received enteral nutritional supply within the first 24 h, and the majority of children were fully enterally fed within the first 10 days. The grade of encephalopathy and mechanical ventilation had a significant influence on the amount of enteral fluids (p = 0.01), whereas the pH and appearance of seizures did not affect the amount of nutritional supply significantly. Furthermore, we did not observe any correlation between enteral intake and abdominal complications such as necrotizing enterocolitis. We observed a large variability of feeding regimes in the four participating NICUs. Early enteral feeding among newborns undergoing TH was performed in each NICU and was well tolerated without increased rates of complications.
Validation of the FACETS-OF-PPC as an Outcome Measure for Children with Severe Neurological Impairment and Their Families—A Multicenter Prospective Longitudinal Study
Authors: Pelke Sophie , Wager Julia , Claus Benedikt B. , Stening Kathrin , Zernikow Boris , Reuther Mandira
Published: October 2021

Outcome measurement in pediatric palliative care (PPC) is receiving increasing attention. The FACETS-OF-PPC, a multidimensional outcome measure for children with severe neurological impairment, has been developed and partly validated. This study aimed to conclude the validity of the German version of the FACETS-OF-PPC. A multicenter prospective study with two points of measurement has been conducted, employing confirmatory factor analyses, reliability analyses, and analyses to evaluate the tool’s sensitivity to change. Overall, 25 inpatient and outpatient teams throughout Germany recruited N = 227 parents of affected children and N = 238 professional caregivers. Participants filled out the FACETS-OF-PPC on the admission of a child to a palliative care service and at discharge from inpatient settings or two months after admission to outpatient services. The analyses revealed the questionnaire needing further adaption. Now, 17 of the original 34 items contribute to the construction of the questionnaire scales. The other items remain part of the questionnaire and may be evaluated descriptively. Furthermore, the FACETS-OF-PPC has moderate to appropriate internal consistency and is sensitive to change. Creating an outcome measure with good psychometric properties for the vulnerable population of children with severe neurological impairment appears extremely difficult. Considering these challenges, the FACETS-OF-PPC demonstrates adequate psychometric properties.
Spatial Warped Gaussian Processes: Estimation and Efficient Field Reconstruction
Authors: Peters Gareth W. , Nevat Ido , Nagarajan Sai Ganesh , Matsui Tomoko
Published: October 2021

A class of models for non-Gaussian spatial random fields is explored for spatial field reconstruction in environmental and sensor network monitoring. The family of models explored utilises a class of transformation functions known as Tukey g-and-h transformations to create a family of warped spatial Gaussian process models which can support various desirable features such as flexible marginal distributions, which can be skewed, leptokurtic and/or heavy-tailed. The resulting model is widely applicable in a range of spatial field reconstruction applications. To utilise the model in applications in practice, it is important to carefully characterise the statistical properties of the Tukey g-and-h random fields. In this work, we study both the properties of the resulting warped Gaussian processes as well as using the characterising statistical properties of the warped processes to obtain flexible spatial field reconstructions. In this regard we derive five different estimators for various important quantities often considered in spatial field reconstruction problems. These include the multi-point Minimum Mean Squared Error (MMSE) estimators, the multi-point Maximum A-Posteriori (MAP) estimators, an efficient class of multi-point linear estimators based on the Spatial-Best Linear Unbiased (S-BLUE) estimators, and two multi-point threshold exceedance based estimators, namely the Spatial Regional and Level Exceedance estimators. Simulation results and real data examples show the benefits of using the Tukey g-and-h transformation as opposed to standard Gaussian spatial random fields in a real data application for environmental monitoring.
Economic and Life Cycle Analysis of Passive and Active Monitoring of Ozone for Forest Protection
Authors: Carrari Elisa , De Marco Alessandra , Laschi Andrea , Badea Ovidiu , Dalstein-Richier Laurence , Fares Silvano , Leca Stefan , Marchi Enrico , Sicard Pierre , Popa Ionel , Hoshika Yasutomo , Materassi Alessandro , Pallante Giacomo , Pitar Diana , Paoletti Elena
Published: October 2021

At forest sites, phytotoxic tropospheric ozone (O3) can be monitored with continuously operating, active monitors (AM) or passive, cumulative samplers (PM). For the first time, we present evidence that the sustainability of active monitoring is better than that of passive sensors, as the environmental, economic, and social costs are usually lower in the former than in the latter. By using data collected in the field, environmental, social, and economic costs were analyzed. The study considered monitoring sites at three distances from a control station in Italy (30, 400, and 750 km), two forest types (deciduous and Mediterranean evergreen), and three time windows (5, 10, and 20 years of monitoring). AM resulted in more convenience than PM, even after 5 years, in terms of O3 depletion, global warming, and photochemical O3 creation potential, suggesting that passive monitoring of ozone is not environmentally sustainable, especially for long time periods. AM led to savings ranging from a minimum of EUR 9650 in 5 years up to EUR 94,796 in 20 years in evergreen forests. The resulting social cost of PM was always higher than that of AM. The present evaluation will help in the decision process for the set-up of long-term forest monitoring sites dedicated to the protection of forests from O3.
Ultrasonic Microwave-Assisted Micelle Combined with Fungal Pretreatment of Eucommia ulmoides Leaves Significantly Improved the Extraction Efficiency of Total Flavonoids and Gutta-Percha
Authors: Wu Mingfang , Liu Peiyan , Wang Siying , Zhong Chen , Zhao Xiuhua
Published: October 2021

A biological pretreatment of Eucommia ulmoides leaf biomass was carried out. Above all, the total flavonoids were isolated from Eucommia ulmoides leaves by the treatment of alkaline solution of sodium dodecyl benzene sulfonate combined with ultrasonic microwave. The extraction parameters were optimized by central composite design (CCD) software and were displayed as follows: surfactant concentration of 1.5%, microwave power of 700 W, extraction time of 30 min, and liquid–solid ratio of 50 mL/g. The actual yield of total flavonoids was 1.45%. The results of Sudan III color development showed that the cuticle of Eucommia ulmoides leaves was completely removed after dilute alkali pretreatment. Then, Eucommia ulmoides leaves were fermented by Trichoderma viride to remove the holocellulose and obtain gutta-percha. The content of cellulose and hemicellulose in Eucommia ulmoides leaves obviously decreased after Trichoderma viride fermentation. The optimum parameters were listed as follows: solid–liquid ratio of 0.06 g/mL, four extraction times, extraction time of 89.72 min, and extraction temperature of 85 °C. The actual yield of gutta-percha was 4.38%. The amount of extraction solvent per unit weight of gutta-percha from untreated Eucommia ulmoides leaves was 2.91 mL/mg, while that from leaves treated by Trichoderma viride was only 0.96 mL/mg. The amount of extraction solvent was grossly reduced, which is beneficial in terms of environmental protection. The characterizations of gutta-percha were verified by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and proton nuclear magnetic resonance (1H NMR). This study laid a certain theoretical and experimental basis for the multi-stage extraction of Eucommia ulmoides leaves and the utilization of Eucommia ulmoides resources.