bluuebunny/crossref_metadata_2025 huggingface dataset:
The Antidepressant Mirtazapine Rapidly Shifts Hepatic B Cell Populations and Functional Cytokine Signatures in the Mouse
Authors: Almishri Wagdi , Davis Rachelle P. , Shaheen Abdel-Aziz , Altonsy Mohammed O. , Jenne Craig N. , Swain Mark G.
Published: March 2021

Introduction

B cells are important regulators of both adaptive and innate immunity. The normal liver contains significant numbers of B cells, and their numbers increase dramatically in immune-mediated liver diseases. Our previous observations suggest a hepatoprotective effect of the antidepressant mirtazapine in human and experimental immune-mediated liver disease. Therefore, we performed a series of experiments to determine the impact of mirtazapine treatment on hepatic B cell homeostasis, as reflected by B cell number, trafficking and phenotype using flow cytometry (FCM) and intravital microscopy (IVM) analysis. Mirtazapine treatment rapidly induced a significant reduction in total hepatic B cell numbers, paralleled by a compositional shift in the predominant hepatic B cell subtype from B2 to B1. This shift in hepatic B cells induced by mirtazapine treatment was associated with a striking increase in total hepatic levels of the chemokine CXCL10, and increased production of CXCL10 by hepatic macrophages and dendritic cells. Furthermore, mirtazapine treatment led to an upregulation of CXCR3, the cognate chemokine receptor for CXCL10, on hepatic B cells that remained in the liver post-mirtazapine. A significant role for CXCR3 in the hepatic retention of B cells post-mirtazapine was confirmed using CXCR3 receptor blockade. In addition, B cells remaining in the liver post-mirtazapine produced lower amounts of the proinflammatory Th1-like cytokines IFNγ, TNFα, and IL-6, and increased amounts of the Th2-like cytokine IL-4, after stimulation in vitro.

Conclusion

Mirtazapine treatment rapidly alters hepatic B cell populations, enhancing hepatic retention of CXCR3-expressing innate-like B cells that generate a more anti-inflammatory cytokine profile. Mirtazapine-induced hepatic B cell shifts could potentially represent a novel therapeutic approach to immune-mediated liver diseases characterized by B cell driven pathology.
Comparative Analysis of Global Proteome and Lysine Acetylome Between Naive CD4+ T Cells and CD4+ T Follicular Helper Cells
Authors: Zhao Ming , Jia Sujie , Gao Xiaofei , Qiu Hong , Wu Ruifang , Wu Haijing , Lu Qianjin
Published: March 2021

As a subgroup of CD4+ T helper cells, follicular helper T (Tfh) cells provide help to germinal center B cells and mediate the development of long-lived humoral immunity. Dysregulation of Tfh cells is associated with several major autoimmune diseases. Although recent studies showed that Tfh cell differentiation is controlled by the transcription factor Bcl6, cytokines, and cell-cell signals, limited information is available on the proteome and post-translational modifications (PTMs) of proteins in human Tfh cells. In the present study, we investigated quantitative proteome and acetylome in human naive CD4+ T cells and in vitro induced Tfh (iTfh) cells using the tandem mass tag (TMT) labeling technique, antibody-based affinity enrichment, and high-resolution liquid chromatography-mass spectrometry (LC-MS)/mass spectrometry (MS) analysis. In total, we identified 802 upregulated proteins and 598 downregulated proteins at the threshold of 1.5-fold in iTfh cells compared to naive CD4+ T cells. With the aid of intensive bioinformatics, the biological process, the cellular compartment, the molecular function, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein–protein interaction of these differentially expressed proteins were revealed. Moreover, the acetylome data showed that 22 lysine (K) acetylated proteins are upregulated and 26 K acetylated proteins are downregulated in iTfh cells compared to the naive CD4+ T cells, among which 11 differentially acetylated K residues in core histones were identified, indicating that protein acetylation and epigenetic mechanism are involved in regulating Tfh cell differentiation. The study provides some important clues for investigating T cell activation and Tfh cell differentiation.
Impact of Active Control Turbocharging on the Fuel Economy and Emissions of a Light-Duty Reactivity Controlled Compression Ignition Engine: A Simulation Study
Authors: Bharath Anand Nageswaran , Reitz Rolf D. , Rutland Christopher J.
Published: March 2021

While forced induction strategies such as turbocharging can increase the power output and extend the load limit of engines operating on low temperature combustion strategies such as reactivity controlled compression ignition, the low exhaust enthalpy prevalent in these strategies requires the use of high backpressures to attain high turbocharger efficiencies, leading to high pumping losses and in turn poor fuel economy. Hence, there is a need to improve the exhaust energy utilization by the turbocharger such that the negative effects of the high backpressure requirements are offset. One turbocharger operating strategy that has the potential to enhance exhaust enthalpy conversion by the turbine is active control turbocharging (ACT), in which the rack position of a variable geometry turbocharger (VGT) is actuated using a continuously varying sinusoidal signal whose frequency is proportional to engine speed. In this study, the impact of ACT on turbocharger performance and fuel economy of a light-duty reactivity controlled compression ignition engine equipped with a VGT is investigated through coupled GT-POWER/KIVA-3V simulations at a medium-load cruise operating condition. A design of experiments study was executed in which the rack position amplitude and phase angle were independently varied, and the turbine efficiency, compressor efficiency, crankshaft torque, and brake specific fuel consumption were tracked for each run. The results show that ACT operation significantly increased the torque output while improving fuel economy over baseline VGT operation, but the range of actuation signal amplitude ratio was limited to 40% of the maximum amplitude possible due to peak cylinder pressure and peak pressure rise rate constraints. It is also shown that the impact of signal phase angle on turbocharger efficiency and overall system performance is not as significant as the amplitude ratio. The best fuel economy improvement over the baseline VGT operation at cruise conditions was observed at 40% amplitude ratio and 0° phase angle, and this value was 2.8%.
Advanced Life Support vs. Basic Life Support for Patients With Trauma in Prehospital Settings: A Systematic Review and Meta-Analysis
Authors: Kondo Yutaka , Fukuda Tatsuma , Uchimido Ryo , Kashiura Masahiro , Kato Soichiro , Sekiguchi Hiroshi , Zamami Yoshito , Hifumi Toru , Hayashida Kei
Published: March 2021

Background: Advanced Life Support (ALS) is regarded to be associated with improved survival in pre-hospital trauma care when compared to Basic Life Support (BLS) irrespective of lack of evidence. The aim of this study is to ascertain ALS improves survival for trauma in prehospital settings when compared to BLS.

Methods: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for published controlled trials (CTs), and observational studies that were published until Aug 2017. The population of interest were adults (>18 years old) trauma patients who were transported by ground transportation and required resuscitation in prehospital settings. We compared outcomes between the ALS and BLS groups. The primary outcome was in-hospital mortality and secondary outcomes were neurological outcome and time spent on scene.

Results: We identified 2,502 studies from various databases and 10 studies were included in the analysis (two CTs, and eight observational studies). The outcomes were not statistically significant between the ALS and BLS groups (pooled OR 1.14; 95% CI 0.95 to 1.36 for mortality, pooled OR 1.12; 95% CI 0.88 to 1.42 for good neurological outcomes, pooled mean difference −0.96; 95% CI−6.64 to 4.72 for on-scene time) in CTs. In observational studies, ALS prolonged on-scene time and increased mortality (pooled OR 1.56; 95% CI: 1.31 to 1.86 for mortality, and pooled mean difference, 1.26; 95% CI: 0.07 to 2.45 for on-scene time).

Conclusions: In prehospital settings, the present study showed no advantages of ALS on the outcomes in patients with trauma compared to BLS.
Perspectives on RNA Vaccine Candidates for COVID-19
Authors: Borah Pobitra , Deb Pran Kishore , Al-Shar’i Nizar A. , Dahabiyeh Lina A. , Venugopala Katharigatta N. , Singh Vinayak , Shinu Pottathil , Hussain Snawar , Deka Satyendra , Chandrasekaran Balakumar , Jaradat Da’san M. M.
Published: March 2021

With the current outbreak caused by SARS-CoV-2, vaccination is acclaimed as a public health care priority. Rapid genetic sequencing of SARS-CoV-2 has triggered the scientific community to search for effective vaccines. Collaborative approaches from research institutes and biotech companies have acknowledged the use of viral proteins as potential vaccine candidates against COVID-19. Nucleic acid (DNA or RNA) vaccines are considered the next generation vaccines as they can be rapidly designed to encode any desirable viral sequence including the highly conserved antigen sequences. RNA vaccines being less prone to host genome integration (cons of DNA vaccines) and anti-vector immunity (a compromising factor of viral vectors) offer great potential as front-runners for universal COVID-19 vaccine. The proof of concept for RNA-based vaccines has already been proven in humans, and the prospects for commercialization are very encouraging as well. With the emergence of COVID-19, mRNA-1273, an mRNA vaccine developed by Moderna, Inc. was the first to enter human trials, with the first volunteer receiving the dose within 10 weeks after SARS-CoV-2 genetic sequencing. The recent interest in mRNA vaccines has been fueled by the state of the art technologies that enhance mRNA stability and improve vaccine delivery. Interestingly, as per the “Draft landscape of COVID-19 candidate vaccines” published by the World Health Organization (WHO) on December 29, 2020, seven potential RNA based COVID-19 vaccines are in different stages of clinical trials; of them, two candidates already received emergency use authorization, and another 22 potential candidates are undergoing pre-clinical investigations. This review will shed light on the rationality of RNA as a platform for vaccine development against COVID-19, highlighting the possible pros and cons, lessons learned from the past, and the future prospects.
Eugene P. Kennedy’s Legacy: Defining Bacterial Phospholipid Pathways and Function
Authors: Dowhan William , Bogdanov Mikhail
Published: March 2021

In the 1950’s and 1960’s Eugene P. Kennedy laid out the blueprint for phospholipid biosynthesis in somatic cells andEscherichia coli, which have been coined the Kennedy Pathways for phospholipid biosynthesis. His research group continued to make seminal contributions in the area of phospholipids until his retirement in the early 1990’s. During these years he mentored many young scientists that continued to build on his early discoveries and who also mentored additional scientists that continue to make important contributions in areas related to phospholipids and membrane biogenesis. This review will focus on the initialE. coliKennedy Pathways and how his early contributions have laid the foundation for our current understanding of bacterial phospholipid genetics, biochemistry and function as carried on by his scientific progeny and others who have been inspired to study microbial phospholipids.
The Panopticon—Assessing the Effect of Starvation on Prolonged Fly Activity and Place Preference
Authors: Mahishi Deepthi , Triphan Tilman , Hesse Ricarda , Huetteroth Wolf
Published: March 2021

Animal behaviours are demonstrably governed by sensory stimulation, previous experience and internal states like hunger. With increasing hunger, priorities shift towards foraging and feeding. During foraging, flies are known to employ efficient path integration strategies. However, general long-term activity patterns for both hungry and satiated flies in conditions of foraging remain to be better understood. Similarly, little is known about how permanent contact chemosensory stimulation affects locomotion. To address these questions, we have developed a novel, simplistic fly activity tracking setup—the Panopticon. Using a 3D-printed Petri dish inset, our assay allows recording of walking behaviour, of several flies in parallel, with all arena surfaces covered by a uniform substrate layer. We tested two constellations of providing food: (i) in single patches and (ii) omnipresent within the substrate layer. Fly tracking is done with FIJI, further assessment, analysis and presentation is done with a custom-built MATLAB analysis framework. We find that starvation history leads to a long-lasting reduction in locomotion, as well as a delayed place preference for food patches which seems to be not driven by immediate hunger motivation.
Dominant and Modifiable Risk Factors for Dementia in Sub-Saharan Africa: A Systematic Review and Meta-Analysis
Authors: Ojagbemi Akin , Okekunle Akinkunmi Paul , Babatunde Opeyemi
Published: March 2021

Background: Sub-Saharan Africa (SSA) is projected to have a rapid increase in the number of people living with dementia by 2050. Yet, there is currently no robust evidence on the risk factors for dementia in the sub-region that could inform context specific interventions.

Methods: We conducted a systematic review and meta-analysis of observational studies to determine the dominant and modifiable risk factors for dementia in SSA. We searched MEDLINE, EMBASE, PsychINFO, and African Journals Online using keywords for dementia and Alzheimer's disease as well as the.mp operator for all 47 SSA countries or regions. We included peer-reviewed original studies with epidemiological designs, conducted random effect meta-analysis and determined the dominant and modifiable risk factors for dementia using the inverse of variance method.

Results: A total of 44 studies out of 2,848 met criteria for syntheses. The pooled annual incidence of dementia from 5,200 cohort risk years was 2.0% [(95% Confidence Interval (CI) = 1.0–4.0%)]. The pooled prevalence was 5.0% (95% CI = 2.0–7.0%). Older age was the dominant risk factor for both prevalent [(Standard error (S.E = 0.3, weight = 25.2%)] and incident dementia (S.E = 0.02, weight = 95.8%), while low educational attainment (S.E = 0.19, weight = 32.6%) and poor predementia cognitive functioning at baseline (S.E = 0.2, weight = 20.5%) were the best ranked modifiable risk factor for incident dementia.

Conclusion: Low formal educational attainment which, in SSA, may represent a stable index of low socioeconomic position and health disadvantage over the life course, was the most prominent modifiable risk factor for incident dementia. Findings have implications for deliberate policies targeted at access to education across the life course as a primary prevention strategy against dementia in SSA.
Early Post-operative CT-Angiography Imaging After EC-IC Bypass Surgery in Moyamoya Patients
Authors: Hurth Helene , Hauser Till-Karsten , Haas Patrick , Wang Sophie , Mengel Annerose , Tatagiba Marcos , Ernemann Ulrike , Khan Nadia , Roder Constantin
Published: March 2021

Objective: To evaluate the clinical value of early post-operative computed tomographic angiography (CTA) after direct extracranial-intracranial (EC-IC) bypass surgery in moyamoya patients.

Methods: A retrospective analysis of all adult moyamoya patients treated at our center from 2013 to 2019 with a direct EC-IC bypass was performed. Early post-operative CTA (within 24 h after surgery) was compared with conventional digital subtraction angiography (DSA) 6–12 months after surgery. If available, magnetic resonance time-of-flight angiography (MR-TOF) was evaluated 3 months and 6–12 months post-operatively as well. Imaging results were analyzed and compared with CTA, MR-TOF and DSA, whereat DSA was used as the final and definite modality to decide on bypass patency.

Results: A total of 103 direct EC-IC bypasses in 63 moyamoya patients were analyzed. All inclusion criteria were met in 32 patients (53 direct bypasses). In 84.9% the bypass appeared definitively, in 5.7% uncertainly and in 9.4% not patent according to early post-operative CTA. MR-TOF suggested definitive bypass patency in 86.8% 3 months after surgery and in 93.5% 6–12 months after surgery. DSA 6–12 months post-operatively showed a patency in 98.1% of all bypasses. The positive predictive value (to correctly detect an occluded bypass) on post-operative CTA was 12.5%, the negative predictive value (to correctly detect a patent bypass) was 100% with a sensitivity of 100% and a specificity of 86.5%.

Conclusion: Early post-operative CTA has a high predictive value to confirm the patency of a bypass. On the other hand, a high false positive rate of (according to CTA) occluded bypasses after direct EC-IC bypass surgery can be seen. This must be considered critically when initiating possible therapeutic measures.
Is Neuromorphic MNIST Neuromorphic? Analyzing the Discriminative Power of Neuromorphic Datasets in the Time Domain
Authors: Iyer Laxmi R. , Chua Yansong , Li Haizhou
Published: March 2021

A major characteristic of spiking neural networks (SNNs) over conventional artificial neural networks (ANNs) is their ability to spike, enabling them to use spike timing for coding and efficient computing. In this paper, we assess if neuromorphic datasets recorded from static images are able to evaluate the ability of SNNs to use spike timings in their calculations. We have analyzed N-MNIST, N-Caltech101 and DvsGesture along these lines, but focus our study on N-MNIST. First we evaluate if additional information is encoded in the time domain in a neuromorphic dataset. We show that an ANN trained with backpropagation on frame-based versions of N-MNIST and N-Caltech101 images achieve 99.23 and 78.01% accuracy. These are comparable to the state of the art—showing that an algorithm that purely works on spatial data can classify these datasets. Second we compare N-MNIST and DvsGesture on two STDP algorithms, RD-STDP, that can classify only spatial data, and STDP-tempotron that classifies spatiotemporal data. We demonstrate that RD-STDP performs very well on N-MNIST, while STDP-tempotron performs better on DvsGesture. Since DvsGesture has a temporal dimension, it requires STDP-tempotron, while N-MNIST can be adequately classified by an algorithm that works on spatial data alone. This shows that precise spike timings are not important in N-MNIST. N-MNIST does not, therefore, highlight the ability of SNNs to classify temporal data. The conclusions of this paper open the question—what dataset can evaluate SNN ability to classify temporal data?
Motor Imagery EEG Signal Recognition Using Deep Convolution Neural Network
Authors: Xiao Xiongliang , Fang Yuee
Published: March 2021

Brain computer interaction (BCI) based on EEG can help patients with limb dyskinesia to carry out daily life and rehabilitation training. However, due to the low signal-to-noise ratio and large individual differences, EEG feature extraction and classification have the problems of low accuracy and efficiency. To solve this problem, this paper proposes a recognition method of motor imagery EEG signal based on deep convolution network. This method firstly aims at the problem of low quality of EEG signal characteristic data, and uses short-time Fourier transform (STFT) and continuous Morlet wavelet transform (CMWT) to preprocess the collected experimental data sets based on time series characteristics. So as to obtain EEG signals that are distinct and have time-frequency characteristics. And based on the improved CNN network model to efficiently recognize EEG signals, to achieve high-quality EEG feature extraction and classification. Further improve the quality of EEG signal feature acquisition, and ensure the high accuracy and precision of EEG signal recognition. Finally, the proposed method is validated based on the BCI competiton dataset and laboratory measured data. Experimental results show that the accuracy of this method for EEG signal recognition is 0.9324, the precision is 0.9653, and the AUC is 0.9464. It shows good practicality and applicability.
Discovery and Pharmacological Evaluation of STEAP4 as a Novel Target for HER2 Overexpressing Breast Cancer
Authors: Orfanou Ioanna-Maria , Argyros Orestis , Papapetropoulos Andreas , Tseleni-Balafouta Sofia , Vougas Konstantinos , Tamvakopoulos Constantin
Published: March 2021

Breast cancer (BC) is a highly heterogeneous disease encompassing multiple subtypes with different molecular and histopathological features, disease prognosis, and therapeutic responses. Among these, the Triple Negative BC form (TNBC) is an aggressive subtype with poor prognosis and therapeutic outcome. With respect to HER2 overexpressing BC, although advanced targeted therapies have improved the survival of patients, disease relapse and metastasis remains a challenge for therapeutic efficacy. In this study the aim was to identify key membrane-associated proteins which are overexpressed in these aggressive BC subtypes and can serve as potential biomarkers or drug targets. We leveraged on the development of a membrane enrichment protocol in combination with the global profiling GeLC-MS/MS technique, and compared the proteomic profiles of a HER2 overexpressing (HCC-1954) and a TNBC (MDA-MB-231) cell line with that of a benign control breast cell line (MCF-10A). An average of 2300 proteins were identified from each cell line, of which approximately 600 were membrane-associated proteins. Our global proteomic methodology in tandem with invigoration by Western blot and Immunofluorescence analysis, readily detected several previously-established BC receptors like HER2 and EPHA2, but importantly STEAP4 and CD97 emerged as novel potential candidate markers. This is the first time that the mitochondrial iron reductase STEAP4 protein up-regulation is linked to BC (HER2+ subtype), while for CD97, its role in BC has been previously described, but never before by a global proteomic technology in TNBC. STEAP4 was selected for further detailed evaluation by the employment of Immunohistochemical analysis of BC xenografts and clinical tissue microarray studies. Results showed that STEAP4 expression was evident only in malignant breast tissues whereas all the benign breast cases had no detectable levels. A functional role of STEAP4 intervention was established in HER2 overexpressing BC by pharmacological studies, where blockage of the STEAP4 pathway with an iron chelator (Deferiprone) in combination with the HER2 inhibitor Lapatinib led to a significant reduction in cell growth in vitro. Furthermore, siRNA mediated knockdown of STEAP4 also suppressed cell proliferation and enhanced the inhibition of Lapatinib in HER2 overexpressing BC, confirming its potential oncogenic role in BC. In conclusion, STEAP4 may represent a novel BC related biomarker and a potential pharmacological target for the treatment of HER2 overexpressing BC.
Metabolic Syndrome and Breast Cancer: Prevalence, Treatment Response, and Prognosis
Authors: Dong Shuwen , Wang Zheng , Shen Kunwei , Chen Xiaosong
Published: March 2021

Metabolic syndrome is a type of multifactorial metabolic disease with the presence of at least three factors: obesity, diabetes mellitus, low high-density lipoprotein, hypertriglyceridemia, and hypertension. Recent studies have shown that metabolic syndrome and its related components exert a significant impact on the initiation, progression, treatment response, and prognosis of breast cancer. Metabolic abnormalities not only increase the disease risk and aggravate tumor progression but also lead to unfavorable treatment responses and more treatment side effects. Moreover, biochemical reactions caused by the imbalance of these metabolic components affect both the host general state and organ-specific tumor microenvironment, resulting in increased rates of recurrence and mortality. Therefore, this review discusses the recent advances in the association of metabolic syndrome and breast cancer, providing potential novel therapeutic targets and intervention strategies to improve breast cancer outcome.
A Multi-Omics Analysis of Metastatic Melanoma Identifies a Germinal Center-Like Tumor Microenvironment in HLA-DR-Positive Tumor Areas
Authors: Gadeyne Laura , Van Herck Yannick , Milli Giorgia , Atak Zeynep Kalender , Bolognesi Maddalena Maria , Wouters Jasper , Marcelis Lukas , Minia Angeliki , Pliaka Vaia , Roznac Jan , Alexopoulos Leonidas G. , Cattoretti Giorgio , Bechter Oliver , Oord Joost Van Den , De Smet Frederik , Antoranz Asier , Bosisio Francesca Maria
Published: March 2021

The emergence of immune checkpoint inhibitors has dramatically changed the therapeutic landscape for patients with advanced melanoma. However, relatively low response rates and a high incidence of severe immune-related adverse events have prompted the search for predictive biomarkers. A positive predictive value has been attributed to the aberrant expression of Human Leukocyte Antigen-DR (HLA-DR) by melanoma cells, but it remains unknown why this is the case. In this study, we have examined the microenvironment of HLA-DR positive metastatic melanoma samples using a multi-omics approach. First, using spatial, single-cell mapping by multiplexed immunohistochemistry, we found that the microenvironment of HLA-DR positive melanoma regions was enriched by professional antigen presenting cells, including classical dendritic cells and macrophages, while a more general cytotoxic T cell exhaustion phenotype was present in these regions. In parallel, transcriptomic analysis on micro dissected tissue from HLA-DR positive and HLA-DR negative areas showed increased IFNγ signaling, enhanced leukocyte adhesion and mononuclear cell proliferation in HLA-DR positive areas. Finally, multiplexed cytokine profiling identified an increased expression of germinal center cytokines CXCL12, CXCL13 and CCL19 in HLA-DR positive metastatic lesions, which, together with IFNγ and IL4 could serve as biomarkers to discriminate tumor samples containing HLA-DR overexpressing tumor cells from HLA-DR negative samples. Overall, this suggests that HLA-DR positive areas in melanoma attract the anti-tumor immune cell infiltration by creating a dystrophic germinal center-like microenvironment where an enhanced antigen presentation leads to an exhausted microenvironment, nevertheless representing a fertile ground for a better efficacy of anti-PD-1 inhibitors due to simultaneous higher levels of PD-1 in the immune cells and PD-L1 in the HLA-DR positive melanoma cells.
Hepatectomy, RFA, and Other Liver Directed Therapies for Treatment of Breast Cancer Liver Metastasis: A Systematic Review
Authors: Rivera Kevin , Jeyarajah Dhiresh Rohan , Washington Kimberly
Published: March 2021

Background

The liver is the second most common site of breast cancer metastasis. Liver directed therapies including hepatic resection, radiofrequency ablation (RFA), transarterial chemo- and radioembolization (TACE/TARE), and hepatic arterial infusion (HAI) have been scarcely researched for breast cancer liver metastasis (BCLM). The purpose of this review is to present the known body of literature on these therapies for BCLM.

Methods

A systematic review was performed with pre-specified search terms using PubMed, MEDLINE, EMBASE, and Cochrane Review resulting in 9,957 results. After review of abstracts and application of exclusion criteria, 51 studies were included in this review.

Results

Hepatic resection afforded the longest median overall survival (mOS) and 5-year survival (45 mo, 41%) across 23 studies. RFA was presented in six studies with pooled mOS and 5-year survival of 38 mo and 11–33%. Disease burden and tumor size was lower amongst hepatic resection and RFA patients. TACE was presented in eight studies with pooled mOS and 1-year survival of 19.6 mo and 32–88.8%. TARE was presented in 10 studies with pooled mOS and 1-year survival of 11.5 mo and 34.5–86%. TACE and TARE populations were selected for chemo-resistant, unresectable disease. Hepatic arterial infusion was presented in five studies with pooled mOS of 11.3 months.

Conclusion

Although further studies are necessary to delineate appropriate usage of liver directed therapies in BCLM, small studies suggest hepatic resection and RFA, in well selected patients, can result in prolonged survival. Longitudinal studies with larger cohorts are warranted to further investigate the effectiveness of each modality.
Role of Lymphadenectomy During Interval Debulking Surgery Performed After Neoadjuvant Chemotherapy in Patients With Advanced Ovarian Cancer
Authors: He Minjun , Lai Yuerong , Peng Hongyu , Tong Chongjie
Published: March 2021

Objective

The role of lymphadenectomy in interval debulking surgery (IDS) performed after neoadjuvant chemotherapy (NACT) in advanced ovarian cancer remains unclear. We aimed to investigate the clinical significance of lymphadenectomy in IDS.

Methods

We retrospectively reviewed and analyzed the data of patients with advanced ovarian cancer who underwent NACT followed by IDS.

Results

In 303 patients receiving NACT-IDS, lymphadenectomy was performed in 127 (41.9%) patients. One hundred and sixty-three (53.8%) patients achieved no gross residual disease (NGRD), and 69 (22.8%) had residual disease < 1 cm, whereas 71 (23.4%) had residual disease ≥ 1cm. No significant difference in progression-free survival (PFS) and overall survival (OS) was observed between the lymphadenectomy group and the no lymphadenectomy group in patients with NGRD, residual disease < 1 cm, and residual disease ≥ 1 cm, respectively. The proportions of pelvic, para-aortic and distant lymph node recurrence were 7.9% (10/127), 4.7% (6/127) and 5.5% (7/127) in the lymphadenectomy group, compared with 5.7% (10/176, P = 0.448), 4.5% (8/176, P = 0.942) and 5.1% (9/176, P = 0.878), respectively, in no lymphadenectomy group. Multivariate analysis identified residual disease ≥ 1 cm [hazard ratios (HR), 4.094; P = 0.008] and elevated CA125 levels after 3 cycles of adjuvant chemotherapy (HR, 2.883; P = 0.004) were negative predictors for OS.

Conclusion

Lymphadenectomy may have no therapeutic value in patients with advanced ovarian cancer underwent NACT-IDS. Our findings may help to better the therapeutic strategy for advanced ovarian cancer. More clinical trials are warranted to further clarify the real role of lymphadenectomy in IDS.
mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications
Authors: Lawal Bashir , Lee Ching-Yu , Mokgautsi Ntlotlang , Sumitra Maryam Rachmawati , Khedkar Harshita , Wu Alexander T.H. , Huang Hsu-Shan
Published: March 2021

Background

The application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities in vitro.

Methods

We used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the in vitro anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.

Results

We identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non–small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI50) = 1.12–3.95 µM; total growth inhibition (TGI) = 3.72–16.60 μM), leukemia (GI50 = 1.20–3.10 µM; TGI = 3.90–12.70 μM), melanoma (GI50 = 1.45–3.59 µM), and renal cancer (GI50 = 1.38–3.40 µM; TGI = 4.84–13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = −11.0 kcal/mol), NOS2 (ΔG = −11.0 kcal/mol), and mTOR (ΔG = −8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.

Conclusion

NSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.
Efficacy and Safety of Monoclonal Antibody Against Calcitonin Gene-Related Peptide or Its Receptor for Migraine: A Systematic Review and Network Meta-analysis
Authors: Wang Xing , Chen Yuqi , Song Jinlei , You Chao
Published: March 2021

Background: The optimal monoclonal antibody against calcitonin gene-related peptide (CGRP) for adult patients with migraine has yet to be determined. Therefore, we aimed to compare the effectiveness of different monoclonal antibodies against CGRP or its receptor for adult patients with migraine through a network meta-analysis of randomized controlled trials.

Methods: We systematically searched the MEDILNE, Embase, ClinicalTrials.gov, and Cochrane Library databases for relevant publications from inception until October 30, 2020. Only randomized clinical trials of adults with migraine that assessed any calcitonin gene-related peptide monoclonal antibody and reported clinical outcomes were included. The primary outcomes were changes in monthly migraine days and treatment-emergent adverse events

Results: We initially retrieved 2,070 publications, and ultimately, 18 randomized clinical trials totaling 8,926 patients were included. In terms of efficacy, eptinezumab (MD −1.43, 95% CrI −2.59 to −0.36), erenumab (MD −1.61, 95% CrI −2.40 to −0.84), fremanezumab (MD −2.19, 95% CrI −3.15 to −1.25), and galcanezumab (MD −2.10, 95% CrI −2.76 to −1.45) significantly reduced MMDs compared with placebo. In terms of safety, only galcanezumab increased the incidences of TEAEs (RR 1.11, 95% CrI 1.01–1.22) and serious adverse events (RR 2.95, 95% CrI 1.41–6.87) compared with placebo.

Conclusion: Most drugs performed similarly and were superior to placebo in most of our analyses. Further head-to-head research on different types of CGRP monoclonal antibodies is necessary to validate the present findings.
Study of the Mechanism of Action of Guanxin Shutong Capsules in the Treatment of Coronary Heart Disease Based on Metabolomics
Authors: Wang Dan , Shi Chang , Ge Zhen-Hua , Wei Yu-Xi , Liu Tian-Tian , Wang Yue , Zhou Xin-Feng , Yang Zi-Jun , Wang Wei-Ting , Zhang Yan-Wen , Zhu Xue-Hui , Zhang Jun , Li Ying , Gong Min , Wu Xiao-Hui , Duan Hong-Quan
Published: March 2021

Background: Guan-Xin-Shu-Tong capsule (GXSTC) is a traditional Chinese medicine (TCM) that has been used to treat coronary heart disease (CHD) for many years in China. However, the holistic mechanism of GXSTC against CHD is still unclear. Therefore, the purpose of this paper was to systematically explore the mechanism of action GXSTC in the treatment of CHD rats using a metabolomics strategy.

Methods: A CHD model was induced by ligation of the left anterior descending coronary artery (LAD). In each group, echocardiography was performed; the contents of creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate transaminase (AST) in serum were determined; and the myocardial infarct size was measured. The metabolites in plasma were analyzed by UHPLC-MS/MS-based untargeted metabolomics. Then, multivariate statistical analysis was performed to screen potential biomarkers associated with the GXSTC treatment in the LAD-induced rat CHD model. Finally, the MetaboAnalyst 4.0 platform was used for metabolic pathway enrichment analysis.

Results: GXSTC was able to regulate the contents of CK, LDH and AST; restore impaired cardiac function; and significantly reduce the myocardial infarction area in model rats. Twenty-two biomarkers and nine metabolic pathways of GXSTC in the treatment of CHD were identified through UHPLC-MS/MS-based untargeted metabolomics analysis.

Conclusion: GXSTC regulates metabolic disorders of endogenous components in LAD-induced CHD rats. The anti-CHD mechanism of GXSTC is mainly related to the regulation of amino acid, lipid and hormonal metabolism. This study provides an overall view of the mechanism underlying the action of GXSTC against CHD.
Entropic Effects of Interacting Particles Diffusing on Spherical Surfaces
Authors: Ledesma-Durán Aldo , Munguía-Valadez J. , Moreno-Razo J. Antonio , Hernández S. I. , Santamaría-Holek I.
Published: March 2021

We present a molecular dynamics and theoretical study on the diffusion of interacting particles embedded on the surface of a sphere. By proposing five different interaction potentials among particles, we perform molecular dynamics simulations and calculate the mean square displacement (MSD) of tracer particles under a crowded regime of high surface density. Results for all the potentials show four different behaviors passing from ballistic and transitory at very short times, to sub-diffusive and saturation behaviors at intermediary and long times. Making use of irreversible thermodynamics theory, we also model the last two stages showing that the crowding induces a sub-diffusion process similar to that caused by particles trapped in cages, and that the saturation of the MSD is due to the existence of an entropic potential that limits the number of accessible states to the particles. By discussing the convenience of projecting the motions of the particles over a plane of observation, consistent with experimental capabilities, we compare the predictions of our theoretical model with the simulations showing that these stages are remarkably well described in qualitative and quantitative terms.
Alteration of Diffusion Capacity After SARS-CoV-2 Infection: A Pathophysiological Approach
Authors: Frija-Masson Justine , Bancal Catherine , Plantier Laurent , Benzaquen Hélène , Mangin Laurence , Penaud Dominique , Arnoult Florence , Flamant Martin , d’Ortho Marie-Pia
Published: March 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected millions of people worldwide, and pneumonia affects 90% of patients. This raises the possibility of millions of people with altered lung function. Few data exist to date on pulmonary function after SARS-CoV-2 infection, but alteration of diffusion capacity of CO (DLCO) is the most frequently described abnormality. First, we present original data on lung function at 3 months after SARS-CoV-2 infection and discuss the effect of using European Coal and Steel Community (ECSC) or Global Lung Function Initiative (GLI) reference equations to diagnose diffusion capacity. Second, we review existing data on DLCO alteration after SARS-CoV-2 infection and discuss the implication of restrictive disorder in DLCO alteration. Last, we discuss the pathophysiology of DLCO alteration and try to disentangle vascular damage and fibrosis.
The Effects of a 10-Week Neuromuscular Training on Postural Control in Elite Youth Competitive Ballroom Dancers: A Randomized Controlled Trial
Authors: Zhang Meiqi , Ma Hongtao , Liu Zhan , Smith Daniel M. , Wang Xiao
Published: March 2021

The purpose of this randomized controlled trial was to evaluate the efficacy of a 10-week neuromuscular training (NMT) program on the postural control of elite youth competitive ballroom dancers. Forty-two dancers (21 couples) were randomly assigned to either the NMT group (n= 22) or the control group (CG;n= 20). Participants in NMT underwent a three-sessions-per-week NMT program for 10 weeks. Testing at baseline and after the 10 weeks intervention included the Y-balance test (YBT) and Modified-Balance Error Scoring System (M-BESS). Results of YBT indicated that NMT participants demonstrated increased reach in the posterolateral and posteromedial directions for the right and left lower limb, whereas no significant change was found in the anterior direction for both limbs. Results of Modified-Balance Error Scoring System (M-BESS) showed that NMT participants displayed significantly decreased errors of the double-leg floor (p= 0.026), single-leg foam (p= 0.010), double-leg foam (p= 0.003), tandem floor (p= 0.031), and tandem foam (p= 0.038), while no significant change was found in single-leg floor performance (p= 0.476). CG participants did not exhibit any significant change during the 10-week period. In summary, the study affirmed that the 10-week NMT program enhanced the postural control performance of youth ballroom dancers and showed effects on ballroom dance-specific performance and lower-limb injury prevention. The results suggest that NMT may be a valuable addition to ballroom dance training regimens.
History and Future Perspectives on the Discipline of Quantitative Systems Pharmacology Modeling and Its Applications
Authors: Azer Karim , Kaddi Chanchala D. , Barrett Jeffrey S. , Bai Jane P. F. , McQuade Sean T. , Merrill Nathaniel J. , Piccoli Benedetto , Neves-Zaph Susana , Marchetti Luca , Lombardo Rosario , Parolo Silvia , Immanuel Selva Rupa Christinal , Baliga Nitin S.
Published: March 2021

Mathematical biology and pharmacology models have a long and rich history in the fields of medicine and physiology, impacting our understanding of disease mechanisms and the development of novel therapeutics. With an increased focus on the pharmacology application of system models and the advances in data science spanning mechanistic and empirical approaches, there is a significant opportunity and promise to leverage these advancements to enhance the development and application of the systems pharmacology field. In this paper, we will review milestones in the evolution of mathematical biology and pharmacology models, highlight some of the gaps and challenges in developing and applying systems pharmacology models, and provide a vision for an integrated strategy that leverages advances in adjacent fields to overcome these challenges.
Dangerous Worldview and Perceived Sociopolitical Control: Two Mechanisms to Understand Trust in Authoritarian Political Leaders in Economically Threatening Contexts
Authors: Torres-Vega Laura C. , Ruiz Josefa , Moya Miguel
Published: March 2021

In this research we analyzed the relationship between threatening economic contexts (i.e., undergoing the economic crisis and having low socioeconomic status) and trust in authoritarian ideologies and leaders, regardless of the left–right political axis. Based on two theoretical approaches (i.e., the dual-process model and the compensatory control model), we argue that this relationship is mediated by dangerous worldview and low perceived sociopolitical control. We conducted two correlational studies with samples of the general population. In Study 1 (N = 185), we found that perceived threat from the economic crisis and low socioeconomic status were correlated with a higher dangerous worldview, which resulted in a more authoritarian ideology (i.e., authoritarianism) and finally in greater trust in an authoritarian political leader. In Study 2 (N = 413), we replicated the findings of Study 1 and demonstrated that low perceived sociopolitical control was associated with higher authoritarianism. Moreover, low perceived sociopolitical control partially mediated the relationship between dangerous worldview and authoritarianism. Overall, our results show that two economically threatening contexts (i.e., the economic crisis and low socioeconomic status) promote authoritarianism and trust in authoritarian leaders (with unspecified political orientation) through psychological processes (i.e., perception of the social world and perceived control). These results are useful to understand and combat the rise of authoritarianism in our societies during financially difficult times such as economic crises.
Skin Conductance Responses of Learner and Licensed Drivers During a Hazard Perception Task
Authors: Chirles Theresa J. , Ehsani Johnathon P. , Kinnear Neale , Seymour Karen E.
Published: March 2021

Background: While advanced driver assistance technologies have the potential to increase safety, there is concern that driver inattention resulting from overreliance on these features may result in crashes. Driver monitoring technologies to assess a driver’s state may be one solution. The purpose of this study was to replicate and extend the research on physiological responses to common driving hazards and examine how these may differ based on driving experience.

Methods: Learner and Licensed drivers viewed a Driving Hazard Perception Task while electrodermal activity (EDA) was measured. The task presented 30 Event (hazard develops) and 30 Non-Event (routine driving) videos. A skin conductance response (SCR) score was calculated for each participant based on the percentage of videos that elicited an SCR.

Results: Analysis of the SCR score during Event videos revealed a medium effect (d = 0.61) of group differences, whereby Licensed drivers were more likely to have an SCR than Learner drivers. Interaction effects revealed Licensed drivers were more likely to have an SCR earlier in the Event videos compared to the end, and the Learner drivers were more likely to have an SCR earlier in the Non-Event videos compared to the end.

Conclusion: Our results support the viability of using SCR during driving videos as a marker of hazard anticipation differing based on experience. The interaction effects may illustrate situational awareness in licensed drivers and deficiencies in sustained vigilance among learner drivers. The findings demand further examination if physiological measures are to be validated as a tool to inform driver potential performance in an increasingly automated driving environment.
Take a “Selfie”: Examining How Leaders Emerge From Leader Self-Awareness, Self-Leadership, and Self-Efficacy
Authors: Bracht Eva M. , Keng-Highberger Fong T. , Avolio Bruce J. , Huang Yiming
Published: March 2021

It is important to understand the processes behind how and why individuals emerge as leaders, so that the best and most capable individuals may occupy leadership positions. So far, most literature in this area has focused on individual characteristics, such as personality or cognitive ability. While interactions between individuals and context do get research attention, we still lack a comprehensive understanding of how the social context at work may help individuals to emerge as leaders. Such knowledge could make an important contribution toward getting the most capable, rather than the most dominant or narcissistic individuals, into leadership positions. In the present work, we contribute toward closing this gap by testing a mediation chain linking a leader's leader self-awareness to a follower's leadership emergence with two time-lagged studies (nstudy1 = 449, nstudy2 = 355). We found that the leader's leader self-awareness was positively related to (a) the follower's leadership emergence and (b) the follower's nomination for promotion and that both relationships were serially mediated by the follower's self-leadership and the follower's leader self-efficacy. We critically discuss our findings and provide ideas for future research.