bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Single-Cell Transcriptomic Analysis of an Anaplastic Oligodendroglioma Post Immunotherapy
Authors: Yu Guangyang , Butler Madison K. , Abdelmaksoud Abdalla , Pang Ying , Su Yu-Ting , Rae Zachary , Dadkhah Kimia , Kelly Michael C. , Song Young K. , Wei Jun S. , Terabe Masaki , Atony Ramya , Mentges Kelly , Theeler Brett J. , Penas-Prado Marta , Butman John , Camphausen Kevin , Zaghloul Kareem A. , Nduom Edjah , Quezado Martha , Aldape Kenneth , Armstrong Terri S. , Gilbert Mark R. , Gulley James L. , Khan Javed , Wu Jing
Published: January 2021

Glioma is the most common primary malignant brain tumor with a poor prognosis. Immune checkpoint inhibitors have been of great interest in investigation of glioma treatments. Here, we report single-cell transcriptomic analyses of two tumor areas from an oligodendroglioma taken from a patient who had multiple tumor recurrences, following several chemotherapies and radiation treatments. The patient subsequently received nivolumab and was considered have disease progression based on conventional diagnostic imaging after two cycles of treatment. He underwent a debulking surgical resection and pathological diagnosis was recurrent disease. During the surgery, tumor tissues were also collected from the enhancing and non-enhancing areas for a scRNAseq analysis to investigate the tumor microenvironment of these radiographically divergent areas. The scRNAseq analysis reveals a plethora of immune cells, suggesting that the increased mass observed on MRI may be partially a result of immune cell infiltration. The patient continued to receive immunotherapy after a short course of palliative radiation and remained free of disease progression for at least 12 months after the last surgery, suggesting a sustained response to immunotherapy. The scRNAseq analysis indicated that the radiological progression was in large part due to immune cell infiltrate and continued immunotherapy led to a positive clinical outcome in a patient who would have otherwise been admitted to hospice care with halting of immunotherapy. Our study demonstrates the potential of scRNAseq analyses in understanding the tumor microenvironment, which may assist the clinical decision-making process for challenging glioma cases following immunotherapy.
Pathway-Based Drug-Repurposing Schemes in Cancer: The Role of Translational Bioinformatics
Authors: Hernández-Lemus Enrique , Martínez-García Mireya
Published: January 2021

Cancer is a set of complex pathologies that has been recognized as a major public health problem worldwide for decades. A myriad of therapeutic strategies is indeed available. However, the wide variability in tumor physiology, response to therapy, added to multi-drug resistance poses enormous challenges in clinical oncology. The last years have witnessed a fast-paced development of novel experimental and translational approaches to therapeutics, that supplemented with computational and theoretical advances are opening promising avenues to cope with cancer defiances. At the core of these advances, there is a strong conceptual shift from gene-centric emphasis on driver mutations in specific oncogenes and tumor suppressors—let us call that the silver bullet approach to cancer therapeutics—to a systemic, semi-mechanistic approach based on pathway perturbations and global molecular and physiological regulatory patterns—we will call this the shrapnel approach. The silver bullet approach is still the best one to follow when clonal mutations in driver genes are present in the patient, and when there are targeted therapies to tackle those. Unfortunately, due to the heterogeneous nature of tumors this is not the common case. The wide molecular variability in the mutational level often is reduced to a much smaller set of pathway-based dysfunctions as evidenced by the well-known hallmarks of cancer. In such cases “shrapnel gunshots” may become more effective than “silver bullets”. Here, we will briefly present both approaches and will abound on the discussion on the state of the art of pathway-based therapeutic designs from a translational bioinformatics and computational oncology perspective. Further development of these approaches depends on building collaborative, multidisciplinary teams to resort to the expertise of clinical oncologists, oncological surgeons, and molecular oncologists, but also of cancer cell biologists and pharmacologists, as well as bioinformaticians, computational biologists and data scientists. These teams will be capable of engaging on a cycle of analyzing high-throughput experiments, mining databases, researching on clinical data, validating the findings, and improving clinical outcomes for the benefits of the oncological patients.
MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways
Authors: Zhang Xu , Wang Jie , Wang Yifeng , Liu Guanzheng , Li Huan , Yu Jiefeng , Wu Runqiu , Liang Jun , Yu Rutong , Liu Xuejiao
Published: January 2021

Glioblastoma multiforme (GBM) is a devastating disease yet no effective drug treatment has been established to date. Glioblastoma stem-like cells (GSCs) are insensitive to treatment and may be one of the reasons for the relapse of GBM. Maternal embryonic leucine zipper kinase gene (MELK) plays an important role in the malignant proliferation and the maintenance of GSC stemness properties of GBM. However, the therapeutic effect of targeted inhibition of MELK on GBM remains unclear. This study analyzed the effect of a MELK oral inhibitor, OTSSP167, on GBM proliferation and the maintenance of GSC stemness. OTSSP167 significantly inhibited cell proliferation, colony formation, invasion, and migration of GBM. OTSSP167 treatment reduced the expression of cell cycle G2/M phase-related proteins, Cyclin B1 and Cdc2, while up-regulation the expression of p21 and subsequently induced cell cycle arrest at the G2/M phase. OTSSP167 effectively prolonged the survival of tumor-bearing mice and inhibited tumor cell growth in in vivo mouse models. It also reduced protein kinase B (AKT) phosphorylation levels by OTSSP167 treatment, thereby disrupting the proliferation and invasion of GBM cells. Furthermore, OTSSP167 inhibited the proliferation, neurosphere formation and self-renewal capacity of GSCs by reducing forkhead box M1 (FOXM1) phosphorylation and transcriptional activity. Interestingly, the inhibitory effect of OTSSP167 on the proliferation of GSCs was 4-fold more effective than GBM cells. In conclusion, MELK inhibition suppresses the growth of GBM and GSCs by double-blocking AKT and FOXM1 signals. Targeted inhibition of MELK may thus be potentially used as a novel treatment for GBM.
Deep Convolutional Neural Network-Based Lymph Node Metastasis Prediction for Colon Cancer Using Histopathological Images
Authors: Kwak Min Seob , Lee Hun Hee , Yang Jae Min , Cha Jae Myung , Jeon Jung Won , Yoon Jin Young , Kim Ha Il
Published: January 2021

Background

Human evaluation of pathological slides cannot accurately predict lymph node metastasis (LNM), although accurate prediction is essential to determine treatment and follow-up strategies for colon cancer. We aimed to develop accurate histopathological features for LNM in colon cancer.

Methods

We developed a deep convolutional neural network model to distinguish the cancer tissue component of colon cancer using data from the tissue bank of the National Center for Tumor Diseases and the pathology archive at the University Medical Center Mannheim, Germany. This model was applied to whole-slide pathological images of colon cancer patients from The Cancer Genome Atlas (TCGA). The predictive value of the peri-tumoral stroma (PTS) score for LNM was assessed.

Results

A total of 164 patients with stages I, II, and III colon cancer from TCGA were analyzed. The mean PTS score was 0.380 (± SD = 0.285), and significantly higher PTS scores were observed in patients in the LNM-positive group than those in the LNM-negative group (P < 0.001). In the univariate analyses, the PTS scores for the LNM-positive group were significantly higher than those for the LNM-negative group (P < 0.001). Further, the PTS scores in lymphatic invasion and any one of perineural, lymphatic, or venous invasion were significantly increased in the LNM-positive group (P < 0.001 and P < 0.001).

Conclusion

We established the PTS score, a simplified reproducible parameter, for predicting LNM in colon cancer using computer-based analysis that could be used to guide treatment decisions. These findings warrant further confirmation through large-scale prospective clinical trials.
Is Testicular Torsion a Real Problem in Pediatric Patients With Cryptorchidism?
Authors: Komarowska Marta Diana , Pawelczyk Alicja , Matuszczak Ewa , Dębek Wojciech , Hermanowicz Adam
Published: January 2021

Purpose: To present management and outcomes of patients with cryptorchidism suffering from testicular torsion.

Methods: This is a retrospective review of pediatric patients with torsion of undescended testes, who were treated between 2009 and 2019. We recorded: the age, symptoms, duration of torsion, results of physical examination, surgery findings, and additional treatment. Additionally, an extensive online literature search, from 2015–2020, was performed to identify other similar case series.

Results: We identified 9 boys with torsion of the undescended gonad, which represented 4.7% of all 192 boys with testicular torsion. The mean age of boys with torsion of undescended testis was 8.7 years. The mean duration of symptoms in our study group was long and it was up to 28.5 h. All patients had inguinal canal exploration. In eight cases, testicular necrosis and primary orchidectomy was performed. Furthermore, 45 cases were identified in the literature and reviewed.

Conclusion: According to clinical experience and available studies, torsion of male undescended gonads is a comparatively rare condition. Nevertheless, diagnosis is still delayed and connected with inevitable orchidectomy.
The Relationship Between Indicators of Nasal Respiratory Function and Spirometric Parameters in Children With Bronchial Asthma
Authors: Krasilnikova Svetlana V. , Khramov Alexey A. , Khramova Regina N. , Ovsyannikov Dmitry Yu. , Daniel-Abu Mojisola I. , Novozhilov Alexey , Shahov Andrey V. , Kubysheva Nailya I. , Eliseeva Tatyana I.
Published: January 2021

Introduction: The relationship between objective indicators of nasal obstruction and airflow limitation in children with bronchial asthma (BA) and allergic rhinitis (AR) has not yet been studied.

Objective: To study the relationship between objective parameters of nasal obstruction and airflow limitation, determined using the methods of anterior active rhinomanometry (AARM) and spirometry in children with BA and AR.

Materials and Methods: Eighty eight children and adolescents with BA and AR, boys−65.9% (58/88), were examined. The median age was 11.09 [10.42; 11.76] years. To determine airflow limitation, the following spirometric parameters were evaluated: forced vital capacity of the lungs (FVC), forced expiratory volume in 1 s (FEV1), the ratio of FEV1/FVC, and maximum expiratory flow at the point 25% of the flow-volume loop (MEF25). Data were recorded both in absolute values and in relative units (% pred). Nasal respiratory function was determined by AARM based on the total nasal airflow (TNAF) in absolute (Pa/cm3/s) and relative units (RTNAF, % pred).

Results: In the general cohort and in boys but not in girls, a statistically significant direct correlation was found between TNAF (Pa/cm3/s) and absolute spirometry parameters of bronchial patency—all had p < 0.01. Also, RTNAF and relative MEF25 values (% pred) in the general cohort were R = 0.22, p = 0.04, and in boys, R = 0.28, p = 0.03. In girls, there was no statistically significant correlation between nasal respiratory function and spirometric parameters, all p > 0.05. Additional analysis of literature was conducted to ascertain that the identified gender differences were not occasional.

Conclusion: The significant positive correlation of absolute values of AARM and spirometric parameters in children with BA and AR was established, which apparently reflects the physical development of children. Of all the relative indicators of spirometry, only MEF25 (% pred), which indirectly reflects the patency of small bronchi, had a distinct direct correlation with RTNAF. These patterns are clearly expressed in boys with BA. In girls with this disease, however, the relationship between nasal respiratory function and spirometric indicators seems to be more complex and requires further study.
COVID-19: Considerations for Children and Families During the Pandemic
Authors: Tang Binzhi , Alam Didarul , Rakib Mejbah Uddin , Li Maojun
Published: January 2021

Coronavirus disease 2019 (COVID-19), a fatal virus caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic across the world. Despite early concerns, children appear to be less susceptible to acquiring SARS-CoV-2 and manifest minor clinical symptoms compared with adults. However, there still exists a risk of physical and psychological health problems in children and their families. In this review, we summarize the existing information about the mechanism of SARS-CoV-2 infection, the epidemiology of COVID-19, and the clinical manifestations, treatments, and further considerations regarding COVID-19 in children.
Sterol 27-Hydroxylase Deficiency as a Cause of Neonatal Cholestasis: Report of 2 Cases and Review of the Literature
Authors: Lipiński Patryk , Klaudel-Dreszler Maja , Ciara Elzbieta , Jurkiewicz Dorota , Płoski Rafał , Cielecka-Kuszyk Joanna , Socha Piotr , Jankowska Irena
Published: January 2021

Introduction: Inborn errors of primary bile acid (BA) synthesis are rare autosomal recessive disorders responsible for 1–2% of cases of neonatal cholestasis. Among them, cerebrotendinous xanthomatosis (CTX) is caused by mutations in the CYP27A1 gene resulting in the impairment of sterol 27-hydroxylase enzyme activity.

Patients and Methods: Here we present the study on two siblings with neonatal cholestasis diagnosed with sterol 27-hydroxylase deficiency. The clinical, biochemical, histological, and molecular presentation at the time of diagnosis and detailed follow-up were described. An extensive overview of the literature regarding patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis was also provided.

Results: Patient 1 presented with cholestatic jaundice since 10 weeks of age and developed the end-stage liver disease requiring liver transplantation at 8 months of age but finally succumbed 3 years post-transplantation due to autoimmune hemolytic anemia and multiorgan failure development. Next-generation sequencing performed post mortem, revealed him to be homozygous for the known pathogenic splicing variant c.1184+1G>A in the CYP27A1 gene. Patient 2 (sibling) presented with cholestatic jaundice since the first day of life. Sanger sequencing of CYP27A1 revealed the same results. Chenodeoxycholic acid treatment was introduced just after diagnosis, at 4 months of age. Fourteen patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis were reported in the literature, in most of them presenting as a self-limiting disease.

Conclusions: An early recognition and treatment initiation in CTX is essential.
Effects of Guanxinshutong Capsules as Complementary Treatment in Patients With Chronic Heart Failure: Study Protocol for a Randomized Controlled Trial
Authors: Wang Yu , Xu Jiaping , Yang Jiehong , Zhang Ling , Pan Yuanjiang , Dou Liping , Zhou Peng , Xu Yizhou , Li Chang , He Yu , Zhou Huifen , Yu Li , Chen Jingwen , Huang Shuwei , Fu Wei , Wan Haitong
Published: January 2021

Chronic heart failure (CHF) is a common cardiovascular disease with high mortality and a poor prognosis, which places heavy burdens upon society and families. Traditional Chinese medicine (TCM) has been used extensively as complementary treatment for CHF. Guanxinshutong (GXST) capsules are used commonly for the treatment of coronary heart disease (CHD). Experimental research and small-sample clinical trials have shown that GXST can attenuate CHF. However, the effects of GXST as complementary medicine in CHF treatment lack high-quality clinical evidence. We have designed a multicenter, randomized, double-blind, placebo-controlled clinical trial that explores the efficacy and safety of using GXST compared with placebo for patients with CHF with reduced left ventricular ejection fraction (LVEF). A total of 480 participants will be assigned randomly to the GXST group or placebo group at a 2:1 ratio. GXST and placebo will be added to standard treatment for 12 weeks, and then followed up for another 40 weeks. The primary outcome is the improvement value of 6-min walk distance, and the secondary outcomes include plasma levels of N-terminal pro-B-type natriuretic peptide, New York Heart Association classification, Minnesota Living with Heart Failure Questionnaire scores, echocardiographic parameters, and clinical endpoint events. Adverse events will be monitored throughout the trial. Data will be analyzed following a predefined statistical analysis plan. This study will show the effects of the specific use of GXST in CHF patients with reduced LVEF. The Research Ethics Committee of the Second Affiliated Hospital of Zhejiang Chinese Medical University has approved this study (2019-Y-003-02). Written informed consent of patients will be required. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR1900023877). Our results will be disseminated to the public through peer-reviewed journals, academic conferences, and the Internet.
IQGAP3 Overexpression Correlates With Poor Prognosis and Radiation Therapy Resistance in Breast Cancer
Authors: Hua Xin , Long Zhi-Qing , Guo Ling , Wen Wen , Huang Xin , Zhang Wen-Wen , Lin Huan-Xin
Published: January 2021

Background: IQ motif-containing GTPase activating protein 3 (IQGAP3), the latest identified member of the IQGAP family, may act as a crucial factor in cancer development and progression; however, its clinical value in breast cancer remains unestablished. We explored the correlation between IQGAP3 expression profile and the clinicopathological features in breast cancer.

Methods: IQGAP3 mRNA and protein levels were detected in breast cancer cell lines and tumor tissues by real-time PCR and western blotting and compared to the normal control groups. Protein expression of IQGAP3 was also evaluated immunohistochemically in archived paraffin-embedded specimens from 257 breast cancer patients, and the associations between IQGAP3 expression level, clinical characteristics, and prognosis were analyzed. We assessed the relationship between IQGAP3 expression and sensitivity to radiation therapy which was determined by subgroup analysis.

Results: IQGAP3 was significantly upregulated in breast cancer cell lines and human tumor tissues at both the mRNA and protein level compared to controls. Additionally, high levels of IQGAP3 expression were detected in 110/257 (42.8%) of archived paraffin-embedded breast cancer specimens. High IQGAP3 expression level was significantly related to clinical stage (p = 0.001), T category (p = 0.002), N category (p = 0.001), locoregional recurrence (p = 0.002), distant metastasis (p = 0.001), and vital status (p = 0.001). Univariate and multivariate statistical analysis showed that IQGAP3 expression was an independent prognostic factor among all 257 breast cancer patients in our cohort (p = 0.003, p = 0.001). Subgroup analysis revealed IQGAP3 expression correlated with radioresistance and was also an independent predictor of radiotherapy outcome.

Conclusion: Our findings suggest that high IQGAP3 expression predicts poor prognosis and radioresistance in breast cancer. Therefore, IQGAP3 may be a reliable prognostic biomarker in breast cancer and could be used to identify patients who may benefit from radiotherapy.
Phytosterols: From Preclinical Evidence to Potential Clinical Applications
Authors: Salehi Bahare , Quispe Cristina , Sharifi-Rad Javad , Cruz-Martins Natália , Nigam Manisha , Mishra Abhay Prakash , Konovalov Dmitryi Alexeevich , Orobinskaya Valeriya , Abu-Reidah Ibrahim M. , Zam Wissam , Sharopov Farukh , Venneri Tommaso , Capasso Raffaele , Kukula-Koch Wirginia , Wawruszak Anna , Koch Wojciech
Published: January 2021

Phytosterols (PSs) are plant-originated steroids. Over 250 PSs have been isolated, and each plant species contains a characteristic phytosterol composition. A wide number of studies have reported remarkable pharmacological effects of PSs, acting as chemopreventive, anti-inflammatory, antioxidant, antidiabetic, and antiatherosclerotic agents. However, PS bioavailability is a key issue, as it can be influenced by several factors (type, source, processing, preparation, delivery method, food matrix, dose, time of administration into the body, and genetic factors), and the existence of a close relationship between their chemical structures (e.g., saturation degree and side-chain length) and low absorption rates has been stated. In this sense, the present review intends to provide in-depth data on PS therapeutic potential for human health, also emphasizing their preclinical effects and bioavailability-related issues.
3-Hydroxyphthalic Anhydride-Modified Chicken Ovalbumin as a Potential Candidate Inhibits SARS-CoV-2 Infection by Disrupting the Interaction of Spike Protein With Host ACE2 Receptor
Authors: Liang Taizhen , Qiu Jiayin , Niu Xiaoge , Ma Qinhai , Zhou Chenliang , Chen Pei , Zhang Qiao , Chen Meiyun , Yang Zifeng , Liu Shuwen , Li Lin
Published: January 2021

The global spread of the novel coronavirus SARS-CoV-2 urgently requires discovery of effective therapeutics for the treatment of COVID-19. The spike (S) protein of SARS-CoV-2 plays a key role in receptor recognition, virus-cell membrane fusion and virus entry. Our previous studies have reported that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) serves as a viral entry inhibitor to prevent several kinds of virus infection. Here, our results reveal that HP-OVA can effectively inhibit SARS-CoV-2 replication and S protein-mediated cell-cell fusion in a dose-dependent manner without obvious cytopathic effects. Further analysis suggests that HP-OVA can bind to both the S protein of SARS-CoV-2 and host angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and disrupt the S protein-ACE2 interaction, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that HP-OVA can serve as a potential therapeutic agent for the treatment of deadly COVID-19.
hiPSC-Derived Neurons Provide a Robust and Physiologically Relevant In Vitro Platform to Test Botulinum Neurotoxins
Authors: Lamotte Juliette Duchesne De , Roqueviere Sylvain , Gautier Hélène , Raban Elsa , Bouré Céline , Fonfria Elena , Krupp Johannes , Nicoleau Camille
Published: January 2021

Botulinum neurotoxins (BoNTs) are zinc metalloproteases that block neurotransmitter release at the neuromuscular junction (NMJ). Their high affinity for motor neurons combined with a high potency have made them extremely effective drugs for the treatment of a variety of neurological diseases as well as for aesthetic applications. Currentin vitroassays used for testing and developing BoNT therapeutics include primary rodent cells and immortalized cell lines. Both models have limitations concerning accuracy and physiological relevance. In order to improve the translational value of preclinical data there is a clear need to use more accurate models such as human induced Pluripotent Stem Cells (hiPSC)-derived neuronal models. In this study we have assessed the potential of four different human iPSC-derived neuronal models including Motor Neurons for BoNT testing. We have characterized these models in detail and found that all models express all proteins needed for BoNT intoxication and showed that all four hiPSC-derived neuronal models are sensitive to both serotype A and E BoNT with Motor Neurons being the most sensitive. We showed that hiPSC-derived Motor Neurons expressed authentic markers after only 7 days of culture, are functional and able to form active synapses. When cultivated with myotubes, we demonstrated that they can innervate myotubes and induce contraction, generating anin vitromodel of NMJ showing dose-responsive sensitivity BoNT intoxication. Together, these data demonstrate the promise of hiPSC-derived neurons, especially Motor Neurons, for pharmaceutical BoNT testing and development.
Intake of Natural Compounds and Circulating microRNA Expression Levels: Their Relationship Investigated in Healthy Subjects With Different Dietary Habits
Authors: Ferrero Giulio , Carpi Sara , Polini Beatrice , Pardini Barbara , Nieri Paola , Impeduglia Alessia , Grioni Sara , Tarallo Sonia , Naccarati Alessio
Published: January 2021

Diet has a strong influence on many physiological processes, which in turn have important implications on a variety of pathological conditions. In this respect, microRNAs (miRNAs), a class of small non-coding RNAs playing a relevant epigenetic role in controlling gene expression, may represent mediators between the dietary intake and the healthy status. Despite great advances in the field of nutri-epigenomics, it remains unclear how miRNA expression is modulated by the diet and, specifically, the intake of specific nutrients. We investigated the whole circulating miRNome by small RNA-sequencing performed on plasma samples of 120 healthy volunteers with different dietary habits (vegans, vegetarians, and omnivores). Dietary intakes of specific nutrients were estimated for each subject from the information reported in the food-frequency questionnaire previously validated in the EPIC study. We focused hereby on the intake of 23 natural compounds (NCs) of the classes of lipids, micro-elements, and vitamins. We identified 78 significant correlations (rho > 0.300, p-value < 0.05) among the estimated daily intake of 13 NCs and the expression levels of 58 plasma miRNAs. Overall, vitamin D, sodium, and vitamin E correlated with the largest number of miRNAs. All the identified correlations were consistent among the three dietary groups and 22 of them were confirmed as significant (p-value < 0.05) by age-, gender-, and body-mass index-adjusted Generalized Linear regression Model analysis. miR-23a-3p expression levels were related with different NCs including a significant positive correlation with sodium (rho = 0.377) and significant negative correlations with lipid-related NCs and vitamin E. Conversely, the estimated intake of vitamin D was negatively correlated with the expression of the highest number of circulating miRNAs, particularly miR-1277-5p (rho = −0.393) and miR-144-3p (rho = −0.393). Functional analysis of the targets of sodium intake-correlated miRNAs highlighted terms related to cardiac development. A similar approach on targets of those miRNAs correlated with vitamin D intake showed an enrichment in genes involved in hormone metabolisms, while the response to chronic inflammation was among the top enriched processes involving targets of miRNAs negatively related with vitamin E intake. Our findings show that nutrients through the habitual diet influence circulating miRNA profiles and highlight that this aspect must be considered in the nutri-epigenomic research.
The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
Authors: Wang Kun , Xu Qiushi , Zhong Hanbing
Published: January 2021

Ibrutinib is an orally bioavailable, irreversible selective Bruton’s tyrosine kinase inhibitor that has demonstrated impressive therapeutic effects in patients with B cell malignancies. However, adverse effects, such as bleeding and hypertension, are also reported, implying that studies on the toxicological effect of ibrutinib on living organisms are needed. Here, we have used zebrafish, a successful model organism for studying toxicology, to investigate the influence of ibrutinib during embryogenesis. We found that ibrutinib had potent toxicity on embryonic development, especially vascular development in zebrafish embryos. We also revealed that ibrutinib perturbed vascular formation by suppressing angiogenesis, rather than vasculogenesis. In addition, ibrutinib exposure led to the collapse of the vascular lumen, as well as reduced proliferation and enhanced apoptosis of vascular endothelial cells. Moreover, the expression of vascular development-related genes was also altered in ibrutinib-treated embryos. To our knowledge, this is the first study to describe the vascular toxicity of ibrutinib in an animal model, providing a theoretical basis for clinical safety guidelines in ibrutinib treatment.
Biological Pathways as Substantiation of the Use of Copper Radioisotopes in Cancer Theranostics
Authors: Niculae Dana , Dusman Ramona , Leonte Radu A. , Chilug Livia E. , Dragoi Cristina M. , Nicolae Alina , Serban Radu M. , Niculae Dragos A. , Dumitrescu Ion B. , Draganescu Doina
Published: January 2021

Copper, a cofactor for many enzymes, is a bioelement that is involved in many main biochemical processes; although high levels of copper promote the proliferation of cancer cells. Further development of radiopharmaceuticals based on copper radioisotopes depend on understanding and taking advantage of its biochemical pathways in oncogenesis. As with other radiometals used in molecular imaging and/or targeted therapy, biological vectors are employed to transport copper radioisotopes to a target, aiming for high specific uptake at tumor sites and precise delivery of ionizing radiation. Evidence of the clinical utility of copper radioisotopes in the ionic form CuCl2 were also proven in an in vivo study of the copper metabolism, guiding personalized copper-chelating treatment in cancer patients and in imaging pathological sites associated with copper imbalance. Five of the copper radioisotopes have gained interest for nuclear medicine applications, based on their emissions, energies, and half-lives, as they can be produced with pharmaceutical-grade quality. The uptake mechanism, kinetics, and metabolic parameters are important findings in molecular imaging, which are decisive when designing individualized targeted radiotherapy for dose calculations of high linear energy transfer Auger electrons and β− emissions of 64Cu and 67Cu. As radiation deposits a high amount of energy within the intra-cellular space, the biochemical involvement of copper determines targets in drug design and validation. The biochemical pathways depict copper metabolism in normal cells and highlight its increased activity in tumor progression and angiogenesis. The avid uptake of copper into inter- and intra-mitochondrial spaces, as constituents of cytochrome C oxidase, substantiate the selection of 64/67CuCl2 as theranostic agents.
Biomolecules as Model Indicators of In Vitro and In Vivo Cold Plasma Safety
Authors: Heslin Caitlin , Boehm Daniela , Gilmore Brendan F. , Megaw Julianne , Freeman Theresa A. , Hickok Noreen J. , Cullen P. J. , Bourke Paula
Published: January 2021

The potential applications for cold plasma in medicine are extensive, from microbial inactivation and induction of apoptosis in cancer cells to stimulating wound healing and enhancing the blood coagulation cascade. The safe bio-medical application of cold plasma and subsequent effect on complex biological pathways requires precision and a distinct understanding of how physiological redox chemistry is manipulated. Chemical modification of biomolecules such as carbohydrates, proteins, and lipids treated with cold plasma have been characterized, however, the context of how alterations of these molecules affect cell behavior or in vivo functionality has not been determined. Thus, this study examines the cytotoxic and mutagenic effects of plasma-treated molecules in vitro using CHO-K1 cells and in vivo in Galleria mellonella larvae. Specifically, albumin, glucose, cholesterol, and arachidonic acid were chosen as representative biomolecules, with established involvement in diverse bioprocesses including; cellular respiration, intracellular transport, cell signaling or membrane structure. Long- and short-term effects depended strongly on the molecule type and the treatment milieu indicating the impact of chemical and physical modifications on downstream biological pathways. Importantly, absence of short-term toxicity did not always correlate with absence of longer-term effects, indicating the need to comprehensively assess ongoing effects for diverse biological applications.
Stretched Exponential Dynamics in Online Article Views
Authors: Kim Yeseul , Weon Byung Mook
Published: January 2021

Article view statistics offers a measure to quantify scientific and public impact of online published articles. Popularity of a paper in online community changes with time. To understand popularity dynamics of article views, we propose a decay dynamics based on a stretched exponential model. We find that a stretched exponent gradually decreases with time after online publication following a power-law scaling. Compared with a simple exponential or biexponential model, a stretched exponential model with a time-dependent exponent well describes long-tailed popularity dynamics of online articles. This result gives a useful insight into how popularity diminishes with time in online community.
Simulating Dynamics of Circulation in the Awake State and Different Stages of Sleep Using Non-autonomous Mathematical Model With Time Delay
Authors: Karavaev Anatoly S. , Ishbulatov Yurii M. , Prokhorov Mikhail D. , Ponomarenko Vladimir I. , Kiselev Anton R. , Runnova Anastasiia E. , Hramkov Alexey N. , Semyachkina-Glushkovskaya Oxana V. , Kurths Jürgen , Penzel Thomas
Published: January 2021

We propose a mathematical model of the human cardiovascular system. The model allows one to simulate the main heart rate, its variability under the influence of the autonomic nervous system, breathing process, and oscillations of blood pressure. For the first time, the model takes into account the activity of the cerebral cortex structures that modulate the autonomic control loops of blood circulation in the awake state and in various stages of sleep. The adequacy of the model is demonstrated by comparing its time series with experimental records of healthy subjects in the SIESTA database. The proposed model can become a useful tool for studying the characteristics of the cardiovascular system dynamics during sleep.
Benefit of Physiologically Variable Over Pressure-Controlled Ventilation in a Model of Chronic Obstructive Pulmonary Disease: A Randomized Study
Authors: Dos Santos Rocha Andre , Südy Roberta , Bizzotto Davide , Kassai Miklos , Carvalho Tania , Dellacà Raffaele L. , Peták Ferenc , Habre Walid
Published: January 2021

Introduction

The advantages of physiologically variable ventilation (PVV) based on a spontaneous breathing pattern have been demonstrated in several respiratory conditions. However, its potential benefits in chronic obstructive pulmonary disease (COPD) have not yet been characterized. We used an experimental model of COPD to compare respiratory function outcomes after 6 h of PVV versus conventional pressure-controlled ventilation (PCV).

Materials and Methods

Rabbits received nebulized elastase and lipopolysaccharide throughout 4 weeks. After 30 days, animals were anesthetized, tracheotomized, and randomized to receive 6 h of physiologically variable (n = 8) or conventional PCV (n = 7). Blood gases, respiratory mechanics, and chest fluoroscopy were assessed hourly.

Results

After 6 h of ventilation, animals receiving variable ventilation demonstrated significantly higher oxygenation index (PaO2/FiO2 441 ± 37 (mean ± standard deviation) versus 354 ± 61 mmHg, p < 0.001) and lower respiratory elastance (359 ± 36 versus 463 ± 81 cmH2O/L, p < 0.01) than animals receiving PCV. Animals ventilated with the variable mode also presented less lung derecruitment (decrease in lung aerated area, –3.4 ± 9.9 versus –17.9 ± 6.7%, p < 0.01) and intrapulmonary shunt fraction (9.6 ± 4.1 versus 17.0 ± 5.8%, p < 0.01).

Conclusion

PVV applied to a model of COPD improved oxygenation, respiratory mechanics, lung aeration, and intrapulmonary shunt fraction compared to conventional ventilation. A reduction in alveolar derecruitment and lung tissue stress leading to better aeration and gas exchange may explain the benefits of PVV.
Ca14-3-3 Interacts With CaWRKY58 to Positively Modulate Pepper Response to Low-Phosphorus Starvation
Authors: Cai Jinsen , Cai Weiwei , Huang Xueying , Yang Sheng , Wen Jiayu , Xia Xiaoqin , Yang Feng , Shi Yuanyuan , Guan Deyi , He Shuilin
Published: January 2021

Low-phosphorus stress (LPS) and pathogen attack are two important stresses frequently experienced by plants in their natural habitats, but how plant respond to them coordinately remains under-investigated. Here, we demonstrate that CaWRKY58, a known negative regulator of the pepper (Capsicum annuum) response to attack by Ralstonia solanacearum, is upregulated by LPS. Virus-induced gene silencing (VIGS) and overexpression of CaWRKY58 in Nicotiana benthamiana plants in combination with chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA) demonstrated that CaWRKY58 positively regulates the response of pepper to LPS by directly targeting and regulating genes related to phosphorus-deficiency tolerance, including PHOSPHATE STARVATION RESPONSE1 (PHR1). Yeast two-hybrid assays revealed that CaWRKY58 interacts with a 14-3-3 protein (Ca14-3-3); this interaction was confirmed by pull-down, bimolecular fluorescence complementation (BiFC), and microscale thermophoresis (MST) assays. The interaction between Ca14-3-3 and CaWRKY58 enhanced the activation of PHR1 expression by CaWRKY58, but did not affect the expression of the immunity-related genes CaNPR1 and CaDEF1, which are negatively regulated by CaWRKY58 in pepper upon Ralstonia solanacearum inoculation. Collectively, our data indicate that CaWRKY58 negatively regulates immunity against Ralstonia solanacearum, but positively regulates tolerance to LPS and that Ca14-3-3 transcriptionally activates CaWRKY58 in response to LPS.
Plastid-Targeted Cyanobacterial Flavodiiron Proteins Maintain Carbohydrate Turnover and Enhance Drought Stress Tolerance in Barley
Authors: Shahinnia Fahimeh , Tula Suresh , Hensel Goetz , Reiahisamani Narges , Nasr Nasrin , Kumlehn Jochen , Gómez Rodrigo , Lodeyro Anabella F. , Carrillo Néstor , Hajirezaei Mohammad R.
Published: January 2021

Chloroplasts, the sites of photosynthesis in higher plants, have evolved several means to tolerate short episodes of drought stress through biosynthesis of diverse metabolites essential for plant function, but these become ineffective when the duration of the stress is prolonged. Cyanobacteria are the closest bacterial homologs of plastids with two photosystems to perform photosynthesis and to evolve oxygen as a byproduct. The presence of Flv genes encoding flavodiiron proteins has been shown to enhance stress tolerance in cyanobacteria. In an attempt to support the growth of plants exposed to drought, the Synechocystis genes Flv1 and Flv3 were expressed in barley with their products being targeted to the chloroplasts. The heterologous expression of both Flv1 and Flv3 accelerated days to heading, increased biomass, promoted the number of spikes and grains per plant, and improved the total grain weight per plant of transgenic lines exposed to drought. Improved growth correlated with enhanced availability of soluble sugars, a higher turnover of amino acids and the accumulation of lower levels of proline in the leaf. Flv1 and Flv3 maintained the energy status of the leaves in the stressed plants by converting sucrose to glucose and fructose, immediate precursors for energy production to support plant growth under drought. The results suggest that sugars and amino acids play a fundamental role in the maintenance of the energy status and metabolic activity to ensure growth and survival under stress conditions, that is, water limitation in this particular case. Engineering chloroplasts by Flv genes into the plant genome, therefore, has the potential to improve plant productivity wherever drought stress represents a significant production constraint.
A Preliminary Investigation of the Association Between Misophonia and Symptoms of Psychopathology and Personality Disorders
Authors: Cassiello-Robbins Clair , Anand Deepika , McMahon Kibby , Brout Jennifer , Kelley Lisalynn , Rosenthal M. Zachary
Published: January 2021

Misophonia is a condition characterized by defensive motivational system emotional responding to repetitive and personally relevant sounds (e.g., eating, sniffing). Preliminary research suggests misophonia may be associated with a range of psychiatric disorders, including personality disorders. However, very little research has used clinician-rated psychometrically validated diagnostic interviews when assessing the relationship between misophonia and psychopathology. The purpose of this study was to extend the early research in this area by examining the relationship between symptoms of misophonia and psychiatric diagnoses in a sample of community adults, using semi-structured diagnostic interviews. Results indicated higher misophonia symptoms were associated with more clinician-rated symptoms of personality disorders, but not other disorders. Anxiety partially mediated the relationship between personality disorder symptoms and misophonia. These results suggest misophonia may be associated with a range of psychiatric symptoms and highlight the role of anxiety in this poorly understood condition.
Proprioception in Action: A Matter of Ecological and Social Interaction
Authors: González-Grandón Ximena , Falcón-Cortés Andrea , Ramos-Fernández Gabriel
Published: January 2021

The aim of this paper is to provide a theoretical and formal framework to understand how the proprioceptive and kinesthetic system learns about body position and possibilities for movement in ongoing action and interaction. Whereas most weak embodiment accounts of proprioception focus on positionalist descriptions or on its role as a source of parameters for internal motor control, we argue that these aspects are insufficient to understand how proprioception is integrated into an active organized system in continuous and dynamic interaction with the environment. Our strong embodiment thesis is that one of the main theoretical principles to understand proprioception, as a perceptual experience within concrete situations, is the coupling with kinesthesia and its relational constitution—self, ecological, and social. In our view, these aspects are underdeveloped in current accounts, and an enactive sensorimotor theory enriched with phenomenological descriptions may provide an alternative path toward explaining this skilled experience. Following O'Regan and Noë (2001) sensorimotor contingencies conceptualization, we introduce three distinct notions of proprioceptive kinesthetic-sensorimotor contingencies (PK-SMCs), which we describe conceptually and formally considering three varieties of perceptual experience in action: PK-SMCs-self, PK-SMCs-self-environment, and PK-SMC-self-other. As a proof of concept of our proposal, we developed a minimal PK model to discuss these elements in detail and show their explanatory value as important guides to understand the proprioceptive/kinesthetic system. Finally, we also highlight that there is an opportunity to develop enactive sensorimotor theory in new directions, creating a bridge between the varieties of experiences of oneself and learning skills.
Developmental Profile of Executive Functioning in School-Age Children From Northeast Brazil
Authors: Guerra Amanda , Hazin Izabel , Guerra Yasmin , Roulin Jean-Luc , Le Gall Didier , Roy Arnaud
Published: January 2021

The development of executive functions (EF) is recognizably correlated to culture, contextual and social factors. However, studies considering all the basic EF are still scarce in Brazil, most notably in the Northeast region, which is known for its social inequality and economic gap. This study aimed to analyze the developmental trajectories and structure of four EF, namely inhibition, flexibility, working memory and planning. In addition, the potential effects of socioeconomic status (SES) and gender were examined. The sample included 230 Brazilian children between 7-12 years old, homogeneously distributed by age, gender and type of school. The EF were assessed through the Brazilian version of the Child Executive Functions Battery (CEF-B). A global effect of age was found for most of the EF measures evaluated. Gender effect was mostly non-significant, except for 4 of the 12 tasks. There was a significant SES effect on 8 tasks, all in favor of private school children. Exploratory factorial and correlation analysis showed a 4-factor EF structure, corroborating the theoretical distribution considered in the CEF-B. A developmental progression is evident in the results for all of the EF measures evaluated. While gender had little influence on EF, SES seems to significantly impact the development of EF. As normative data are still lacking in Northeast Brazil, this study may help to understand EF development trajectories and provide tools for neuropsychological evaluation.
Longitudinal Performance in Basic Numerical Skills Mediates the Relationship Between Socio-Economic Status and Mathematics Anxiety: Evidence From Chile
Authors: Guzmán Bárbara , Rodríguez Cristina , Ferreira Roberto A.
Published: January 2021

Socio-economic status (SES) and mathematical performance seem to be risk factors of mathematics anxiety (MA) in both children and adults. However, there is little evidence about how exactly these three constructs are related, especially during early stages of mathematical learning. In the present study, we assessed longitudinal performance in symbolic and non-symbolic basic numerical skills in pre-school and second grade students, as well as MA in second grade students. Participants were 451 children (average pre-school age = 5 years, 6 months) from 12 schools in Chile, which differed in school vulnerability index (SVI), an indicator of SES. We tested an explanatory model of MA that included SES and longitudinal performance in basic numerical skills as predictors. The results showed a direct effect of SES on MA and a mediating effect of performance in symbolic and non-symbolic comparison tasks in pre-school. However, in second grade, only performance in symbolic comparison significantly mediated the SES-MA relationship. These findings suggest that performance in non-symbolic comparison plays an important role in explaining MA at initial stages, but that its influence is no longer significant by the time children reach formal instruction in second grade. By contrast, as children’s formal educational experience in mathematics increases, MA becomes linked primarily to symbolic numerical tasks. In sum, SES affects MA and this is due in part to the effect of SES on the development of numerical learning in pre-school, which in turn has an impact on subsequent, more complex learning, ultimately leading to differences in MA. We discuss the implications of these findings for preventing and acting upon the emergence of MA.
Dual-Mediation Paths Linking Corporate Social Responsibility to Employee’s Job Performance: A Multilevel Approach
Authors: Fang Miaoying , Fan Peng , Nepal Surya , Chang Po-Chien
Published: January 2021

This study attempts to examine the direct impact of corporate social responsibility (CSR) initiatives on employees’ job performance and the indirect relationships between CSR initiatives on employees’ job performance via industrial relations climate and psychological contract fulfillment. Data were collected from 764 supervisor–subordinate dyads and 271 middle managers from 85 companies. Using a multilevel approach, the results showed that organizational-level CSR was positively related to employees’ job performance. Moreover, the industrial relations climate and psychological contract fulfillment played mediating effects between CSR initiatives and job performance. This study provides novel theoretical evidence for why and how CSR initiatives improve job performance. Theoretical and practical implications for implementing CSR initiatives are discussed.