bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational Analysis of Dynamic Light Exposure of Unicellular Algal Cells in a Flat-Panel Photobioreactor to Support Light-Induced CO2 Bioprocess Development
Authors: Vasile Nicolò S. , Cordara Alessandro , Usai Giulia , Re Angela
Published: April 2021

Cyanobacterial cell factories trace a vibrant pathway to climate change neutrality and sustainable development owing to their ability to turn carbon dioxide-rich waste into a broad portfolio of renewable compounds, which are deemed valuable in green chemistry cross-sectorial applications. Cell factory design requires to define the optimal operational and cultivation conditions. The paramount parameter in biomass cultivation in photobioreactors is the light intensity since it impacts cellular physiology and productivity. Our modeling framework provides a basis for the predictive control of light-limited, light-saturated, and light-inhibited growth of the Synechocystis sp. PCC 6803 model organism in a flat-panel photobioreactor. The model here presented couples computational fluid dynamics, light transmission, kinetic modeling, and the reconstruction of single cell trajectories in differently irradiated areas of the photobioreactor to relate key physiological parameters to the multi-faceted processes occurring in the cultivation environment. Furthermore, our analysis highlights the need for properly constraining the model with decisive qualitative and quantitative data related to light calibration and light measurements both at the inlet and outlet of the photobioreactor in order to boost the accuracy and extrapolation capabilities of the model.
Particle Collection in Imhoff Sedimentation Cones Enriches Both Motile Chemotactic and Particle-Attached Bacteria
Authors: Heins Anneke , Reintjes Greta , Amann Rudolf I. , Harder Jens
Published: April 2021

Marine heterotrophic microorganisms remineralize about half of the annual primary production, with the microbiomes on and around algae and particles having a major contribution. These microbiomes specifically include free-living chemotactic and particle-attached bacteria, which are often difficult to analyze individually, as the standard method of size-selective filtration only gives access to particle-attached bacteria. In this study, we demonstrated that particle collection in Imhoff sedimentation cones enriches microbiomes that included free-living chemotactic bacteria and were distinct from particle microbiomes obtained by filtration or centrifugation. Coastal seawater was collected during North Sea phytoplankton spring blooms, and the microbiomes were investigated using 16S rRNA amplicon sequencing and fluorescence microscopy. Enrichment factors of individual operational taxonomic units (OTUs) were calculated for comparison of fractionated communities after separation with unfractionated seawater communities. Filtration resulted in a loss of cells and yielded particle fractions including bacterial aggregates, filaments, and large cells. Centrifugation had the lowest separation capacity. Particles with a sinking rate of >2.4 m day–1 were collected in sedimentation cones as a bottom fraction and enriched in free-living chemotactic bacteria, i.e., Sulfitobacter, Pseudoalteromonas, and Vibrio. Subfractions of these bottom fractions, obtained by centrifugation, showed enrichment of either free-living or particle-attached bacteria. We identified five distinct enrichment patterns across all separation techniques: mechano-sensitive and mechano-stable free-living bacteria and three groups of particle-attached bacteria. Simultaneous enrichment of particle-attached and chemotactic free-living bacteria in Imhoff sedimentation cones is a novel experimental access to these groups providing more insights into the diversity, structure, and function of particle-associated microbiomes, including members of the phycosphere.
HIV-1 Capsid Core: A Bullet to the Heart of the Target Cell
Authors: Toccafondi Elenia , Lener Daniela , Negroni Matteo
Published: April 2021

The first step of the intracellular phase of retroviral infection is the release of the viral capsid core in the cytoplasm. This structure contains the viral genetic material that will be reverse transcribed and integrated into the genome of infected cells. Up to recent times, the role of the capsid core was considered essentially to protect this genetic material during the earlier phases of this process. However, increasing evidence demonstrates that the permanence inside the cell of the capsid as an intact, or almost intact, structure is longer than thought. This suggests its involvement in more aspects of the infectious cycle than previously foreseen, particularly in the steps of viral genomic material translocation into the nucleus and in the phases preceding integration. During the trip across the infected cell, many host factors are brought to interact with the capsid, some possessing antiviral properties, others, serving as viral cofactors. All these interactions rely on the properties of the unique component of the capsid core, the capsid protein CA. Likely, the drawback of ensuring these multiple functions is the extreme genetic fragility that has been shown to characterize this protein. Here, we recapitulate the busy agenda of an HIV-1 capsid in the infectious process, in particular in the light of the most recent findings.
Effects of Several Classes of Voltage-Gated Ion Channel Conductances on Gamma and Theta Oscillations in a Hippocampal Microcircuit Model
Authors: Olteanu Chris , Habibollahi Forough , French Chris
Published: April 2021

Gamma and theta oscillations have been functionally associated with cognitive processes, such as learning and memory. Synaptic conductances play an important role in the generation of intrinsic network rhythmicity, but few studies have examined the effects of voltage-gated ion channels (VGICs) on these rhythms. In this report, we have used a pyramidal-interneuron-gamma (PING) network consisting of excitatory pyramidal cells and two types of inhibitory interneurons. We have constructed a conductance-based neural network incorporating a persistent sodium current (INaP), a delayed rectifier potassium current (IKDR), a inactivating potassium current (IA) and a hyperpolarization-activated current (IH). We have investigated the effects of several conductances on network theta and gamma frequency oscillations. Variation of all conductances of interest changed network rhythmicity. Theta power was altered by all conductances tested. Gamma rhythmogenesis was dependent on IA and IH. The IKDR currents in excitatory pyramidal cells as well as both types of inhibitory interneurons were essential for theta rhythmogenesis and altered gamma rhythm properties. Increasing INaP suppressed both gamma and theta rhythms. Addition of noise did not alter these patterns. Our findings suggest that VGICs strongly affect brain network rhythms. Further investigations in vivo will be of great interest, including potential effects on neural function and cognition.
Neurotrophic Factor Levels in Preterm Infants: A Systematic Review and Meta-Analysis
Authors: Krey Francieli Cristina , Stocchero Bruna Alvim , Creutzberg Kerstin Camile , Heberle Bernardo Aguzzoli , Tractenberg Saulo Gantes , Xiang Li , Wei Wei , Kluwe-Schiavon Bruno , Viola Thiago Wendt
Published: April 2021

Objectives: Through a systematic review and meta-analysis of the literature we aimed to compare the levels of BDNF, NGF, NT-3, NT-4, and GDNF between human term and preterm infants, and investigate factors implicated in the variability of effect size estimates.

Methods: The analysis was performed in three online databases, MEDLINE Complete, PsycINFO, and CINAHL. A random effects model was used to calculate the standardized mean difference (SMD) of neurotrophic factor levels in preterm infants vs. term within a 95% confidence interval (CI). To explore sources of heterogeneity meta-regression models were implemented.

Results: Sixteen studies were included in this meta-analysis. A combined sample of 1,379 preterm and 1,286 term newborns were evaluated. We identified significant lower BDNF (SMD = −0.32; 95% CI: −0.59, −0.06; p = 0.014) and NT-3 (SMD = −0.31; 95% CI: −0.52, −0.09; p = 0.004) levels in preterm compared to term infants. No significant difference was observed in NGF and NT-4 levels between groups. Given that only two effect sizes were generated for GDNF levels, no meta-analytical model was performed. Meta-regression models revealed sample type (placental tissue, cerebrospinal fluid, peripheral blood, and umbilical cord blood) as a significant moderator of heterogeneity for BDNF meta-analysis. No significant associations were found for gestational week, birth weight, and clinical comorbidity of newborns with effect sizes.

Conclusions: Our findings indicated that lower BDNF and NT-3 levels may be associated with preterm birth. Future studies with larger samples sizes should investigate neurodevelopmental manifestations resulting from neurotrophic factor dysregulation among preterm infants.
EEG Assessment in Patients With Disorders of Consciousness: Aims, Advantages, Limits, and Pitfalls
Authors: Rossi Sebastiano Davide , Varotto Giulia , Sattin Davide , Franceschetti Silvana
Published: April 2021

This study presents a brief review of literature exploring simple EEG-polygraphic examinations and procedures that can be carried out at a patient's bedside. These include EEG with a common electrode array and sleep evaluation. The review briefly discusses more complex analytical techniques, such as the application of advanced EEG signal processing methods developed by our research group, to define what type of consistent markers are suitable for clinical use or to better understand complex patient conditions. These advanced analytical techniques aim to detect relevant EEG-based markers that could be useful in evaluating patients and predicting outcomes. These data could contribute to future developments in research.
Clinical Recognition of Sensory Ataxia and Cerebellar Ataxia
Authors: Zhang Qing , Zhou Xihui , Li Yajun , Yang Xiaodong , Abbasi Qammer H.
Published: April 2021

Ataxia is a kind of external characteristics when the human body has poor coordination and balance disorder, it often indicates diseases in certain parts of the body. Many internal factors may causing ataxia; currently, observed external characteristics, combined with Doctor’s personal clinical experience play main roles in diagnosing ataxia. In this situation, different kinds of diseases may be confused, leading to the delay in treatment and recovery. Modern high precision medical instruments would provide better accuracy but the economic cost is a non-negligible factor. In this paper, novel non-contact sensing technique is used to detect and distinguish sensory ataxia and cerebellar ataxia. Firstly, Romberg’s test and gait analysis data are collected by the microwave sensing platform; then, after some preprocessing, some machine learning approaches have been applied to train the models. For Romberg’s test, time domain features are considered, the accuracy of all the three algorithms are higher than 96%; for gait detection, Principal Component Analysis (PCA) is used for dimensionality reduction, and the accuracies of Back Propagation (BP) neural Network, Support Vector Machine (SVM), and Random Forest (RF) are 97.8, 98.9, and 91.1%, respectively.
Bridging Scales in Alzheimer's Disease: Biological Framework for Brain Simulation With The Virtual Brain
Authors: Stefanovski Leon , Meier Jil Mona , Pai Roopa Kalsank , Triebkorn Paul , Lett Tristram , Martin Leon , Bülau Konstantin , Hofmann-Apitius Martin , Solodkin Ana , McIntosh Anthony Randal , Ritter Petra
Published: April 2021

Despite the acceleration of knowledge and data accumulation in neuroscience over the last years, the highly prevalent neurodegenerative disease of AD remains a growing problem. Alzheimer's Disease (AD) is the most common cause of dementia and represents the most prevalent neurodegenerative disease. For AD, disease-modifying treatments are presently lacking, and the understanding of disease mechanisms continues to be incomplete. In the present review, we discuss candidate contributing factors leading to AD, and evaluate novel computational brain simulation methods to further disentangle their potential roles. We first present an overview of existing computational models for AD that aim to provide a mechanistic understanding of the disease. Next, we outline the potential to link molecular aspects of neurodegeneration in AD with large-scale brain network modeling using The Virtual Brain (www.thevirtualbrain.org), an open-source, multiscale, whole-brain simulation neuroinformatics platform. Finally, we discuss how this methodological approach may contribute to the understanding, improved diagnostics, and treatment optimization of AD.
Mind Wandering Influences EEG Signal in Complex Multimodal Environments
Authors: Gouraud Jonas , Delorme Arnaud , Berberian Bruno
Published: April 2021

The phenomenon of mind wandering (MW), as a family of experiences related to internally directed cognition, heavily influences vigilance evolution. In particular, humans in teleoperations monitoring partially automated fleet before assuming manual control whenever necessary may see their attention drift due to internal sources; as such, it could play an important role in the emergence of out-of-the-loop (OOTL) situations and associated performance problems. To follow, quantify, and mitigate this phenomenon, electroencephalogram (EEG) systems already demonstrated robust results. As MW creates an attentional decoupling, both ERPs and brain oscillations are impacted. However, the factors influencing these markers in complex environments are still not fully understood. In this paper, we specifically addressed the possibility of gradual emergence of attentional decoupling and the differences created by the sensory modality used to convey targets. Eighteen participants were asked to (1) supervise an automated drone performing an obstacle avoidance task (visual task) and (2) respond to infrequent beeps as fast as possible (auditory task). We measured event-related potentials and alpha waves through EEG. We also added a 40-Hz amplitude modulated brown noise to evoke steady-state auditory response (ASSR). Reported MW episodes were categorized between task-related and task-unrelated episodes. We found that N1 ERP component elicited by beeps had lower amplitude during task-unrelated MW, whereas P3 component had higher amplitude during task-related MW, compared with other attentional states. Focusing on parieto-occipital regions, alpha-wave activity was higher during task-unrelated MW compared with others. These results support the decoupling hypothesis for task-unrelated MW but not task-related MW, highlighting possible variations in the “depth” of decoupling depending on MW episodes. Finally, we found no influence of attentional states on ASSR amplitude. We discuss possible reasons explaining why. Results underline both the ability of EEG to track and study MW in laboratory tasks mimicking ecological environments, as well as the complex influence of perceptual decoupling on operators' behavior and, in particular, EEG measures.
A Triple Threat? The Role of Diet, Nutrition, and the Microbiota in T1D Pathogenesis
Authors: Hamilton-Williams Emma E. , Lorca Graciela L. , Norris Jill M. , Dunne Jessica L.
Published: April 2021

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.
Safety and Tolerability of BRAF Inhibitor and BRAF Inhibitor-Based Combination Therapy in Chinese Patients With Advanced Melanoma: A Real World Study
Authors: Liu Xing , Li Jing-jing , Ding Ya , Li Dan-dan , Wen Xi-zhi , Weng De-sheng , Wang Jiu-hong , Jiang Hang , Zhang Xiao-shi
Published: April 2021

The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3–4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3–4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3–4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.
Identification of Mitochondrial-Related Prognostic Biomarkers Associated With Primary Bile Acid Biosynthesis and Tumor Microenvironment of Hepatocellular Carcinoma
Authors: Zhang Tao , Nie Yingli , Gu Jian , Cai Kailin , Chen Xiangdong , Li Huili , Wang Jiliang
Published: April 2021

Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-associated deaths worldwide. Despite great progress in early diagnosis and multidisciplinary tumor management, the long-term prognosis of HCC remains poor. Currently, metabolic reprogramming during tumor development is widely observed to support rapid growth and proliferation of cancer cells, and several metabolic targets that could be used as cancer biomarkers have been identified. The liver and mitochondria are the two centers of human metabolism at the whole organism and cellular levels, respectively. Thus, identification of prognostic biomarkers based on mitochondrial-related genes (Mito-RGs)—the coding-genes of proteins located in the mitochondria—that reflect metabolic changes associated with HCC could lead to better interventions for HCC patients. In the present study, we used HCC data from The Cancer Genome Atlas (TCGA) database to construct a classifier containing 10 Mito-RGs (ACOT7, ADPRHL2, ATAD3A, BSG, FAM72A, PDK3, PDSS1, RAD51C, TOMM34, and TRMU) for predicting the prognosis of HCC by using 10-fold Least Absolute Shrinkage and Selection Operation (LASSO) cross-validation Cox regression. Based on the risk score calculated by the classifier, the samples were divided into high- and low-risk groups. Gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), t-distributed stochastic neighbor embedding (t-SNE), and consensus clusterPlus algorithms were used to identify metabolic pathways that were significantly different between the high- and low-risk groups. We further investigated the relationship between metabolic status and infiltration of immune cells into HCC tumor samples by using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) algorithm combined with the Tumor Immune Estimation Resource (TIMER) database. Our results showed that the classifier based on Mito-RGs could act as an independent biomarker for predicting survival of HCC patients. Repression of primary bile acid biosynthesis plays a vital role in the development and poor prognosis of HCC, which provides a potential approach to treatment. Our study revealed cross-talk between bile acid and infiltration of tumors by immune cells, which may provide novel insight into immunotherapy of HCC. Furthermore, our research may provide a novel method for HCC metabolic therapy based on modulation of mitochondrial function.
Association of Body Mass Index With Somatic Mutations in Breast Cancer
Authors: Chen Bo , Guo Liping , Li Kai , Xiao Weikai , Li Yingzi , Li Cheukfai , Mok Hsiaopei , Cao Li , Lin Jiali , Wei Guangnan , Zhang Guochun , Liao Ning
Published: April 2021

Background

The relationship between body mass index (BMI) and the prognosis or treatment response in patients with breast cancer has been demonstrated in previous studies, but the somatic mutation profiles in breast cancer patients with different BMIs have not been explored.

Methods

In the present study, the somatic mutation profiles in 421 female breast cancer patients who were stratified into three subgroups based on BMI (normal weight, overweight/obese, and underweight) were investigated. Capture-based targeted sequencing was performed using a panel comprising 520 cancer-related genes.

Results

A total of 3547 mutations were detected in 390 genes. In breast cancer patients with different BMI statuses, the tumors exhibited high mutation frequency and burden. TP53 was the most common gene in the three groups, followed by PIK3CA, ERBB2, and CDK12. Meanwhile, the mutation hotspots in TP53 and PIK3CA were the same in the three BMI groups. More JAK1 mutations were identified in underweight patients than those in normal patients. Except for JAK1, differentially mutated genes in postmenopausal patients were completely different from those in premenopausal patients. The distribution of mutation types was significantly different among BMI groups in the postmenopausal group. Underweight patients in the postmenopausal group harbored more TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway.

Conclusions

Our next-generation sequencing (NGS)-based gene panel analysis revealed the gene expression profiles of breast cancer patients with different BMI statuses. Although genes with high mutation frequency and burden were found in different BMI groups, some subtle differences could not be ignored. JAK1 mutations might play a vital role in the progression of breast cancer in underweight patients, and this needs further analysis. Postmenopausal underweight patients with breast cancer have more aggressive characteristics, such as TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway. This study provides new evidence for understanding the characteristics of breast cancer patients with different BMIs.
Characterization of the Tumor Immune Microenvironment in Lung Squamous Cell Carcinoma Using Imaging Mass Cytometry
Authors: Li Ran , Lin Ying , Wang Yu , Wang Shaoyuan , Yang Yang , Mu Xinlin , Chen Yusheng , Gao Zhancheng
Published: April 2021

Background

Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer. The tumor immune microenvironment (TIME) affects the anti-tumor immune response and the patient’s prognosis, although the TIME in LUSC patients is incompletely understood.

Methods

We retrospectively collected surgical specimens from patients with previously untreated primary LUSC. Histopathological examination was used to identify tumor regions and adjacent regions, and imaging mass cytometry was used to characterize the immune cells in those regions. The results were compared between regions and between patients.

Results

We identified heterogeneity in the TIME on comparing different patients with LUSC, although the tumor region and adjacent region both exhibited an immune response to the tumor. The TIME typically included a large number of infiltrating and activated T-cells, especially CD8+ T-cells, which closely interacted with the tumor cells in the tumor region. There was limited infiltration of B-cells, NK cells, and NKT cells, while the major immune suppressor cells were CD33+ myeloid-derived cells. We also identified a novel population of CD3−CD4+ cells with high expression of Foxp3 and TNFα, which might modulate the tumor microenvironment and play a proinflammatory role in the TIME.

Conclusions

The TIME of LUSC appears to be immunogenic and heterogenous, with predominant infiltration of activated CD8+ T-cells. The interactions between the tumor cells and T-cells facilitate the anti-tumor activity. A novel subpopulation of CD3−CD4+ cells with high TNFα and Foxp3 expression may modulate the tumor microenvironment and play a proinflammatory role.
The MYH9 Cytoskeletal Protein Is a Novel Corepressor of Androgen Receptors
Authors: Liu Chunhua , Liao Zhaoping , Duan Xiuzhi , Yu Pan , Kong Piaoping , Tao Zhihua , Liu Weiwei
Published: April 2021

In the progression of castration-resistant prostate cancer (CRPC), the androgen receptor (AR) that serves as a transcription factor becomes the most remarkable molecule. The transcriptional activity of AR is regulated by various coregulators. As a result, altered expression levels, an aberrant location or activities of coregulators promote the development of prostate cancer. We describe herein results showing that compared with androgen-dependent prostate cancer (ADPC) cells, AR nuclear translocation capability is enhanced in androgen-independent prostate cancer (AIPC) cells. To gain insight into whether AR coregulators are responsible for AR translocation capability, we performed coimmunoprecipitation (CO-IP) coupled with LC-MS/MS to screen 27 previously reported AR cofactors and 46 candidate AR cofactors. Furthermore, one candidate, myosin heavy chain 9 (MYH9), was identified and verified as a novel AR cofactor. Interestingly, the distribution of MYH9 was in both the cytoplasmic and nuclear compartments yet was enriched in the nucleus when AR was knocked down by AR shRNA, suggesting that the nuclear translocation of MYH9 was negatively regulated by AR. In addition, we found that blebbistatin, an inhibitor of MYH9, not only promoted AR nuclear translocation but also enhanced the expression of the AR target gene PSA, which indicates that MYH9 represses nuclear AR signaling. Taken together, our findings reveal that MYH9 appears to be a novel corepressor of AR plays a pivotal role in the progression of CRPC.
Use of Chronic Prescription Medications and Prevalence of Polypharmacy in Survivors of Childhood Cancer
Authors: Ewig Celeste L. Y. , Cheng Yi Man , Li Hoi Shan , Wong Jasper Chak Ling , Cho Alex Hong Yu , Poon Freddie Man Hong , Li Chi Kong , Cheung Yin Ting
Published: April 2021

Background

As survivors of childhood cancer age, development of cancer treatment-related chronic health conditions often occur. This study aimed to describe the pattern of chronic prescription medication use and identify factors associated with polypharmacy among survivors of childhood cancer.

Methods

This was a retrospective study conducted at the pediatric oncology long-term follow-up clinic in Hong Kong. Eligible subjects included survivors who were (1) diagnosed with cancer before 18 years old, (2) were at least 3 years post-cancer diagnosis and had completed treatment for at least 30 days, and (3) receiving long-term follow-up care at the study site between 2015 and 2018. Dispensing records of eligible survivors were reviewed to identify medications taken daily for ≥30 days or used on an “as needed” basis for ≥6 months cumulatively within the past 12-month period. Polypharmacy was defined as the concurrent use of ≥5 chronic medications. Multivariable log-binomial modeling was conducted to identify treatment and clinical factors associated with medication use pattern and polypharmacy.

Results

This study included 625 survivors (mean current age = 17.9 years, standard deviation [SD] = 7.2 years) who were 9.2 [5.2] years post-treatment. Approximately one-third (n = 219, 35.0%) of survivors were prescribed at least one chronic medication. Frequently prescribed medication classes include systemic antihistamines (26.5%), sex hormones (19.2%), and thyroid replacement therapy (16.0%). Overall prevalence of polypharmacy was 5.3% (n = 33). A higher rate of polypharmacy was found in survivors of CNS tumors (13.6%) than in survivors of hematological malignancies (4.3%) and other solid tumors (5.3%) (P = .0051). Higher medication burden was also observed in survivors who had undergone cranial radiation (RR = 6.31; 95% CI = 2.75–14.49) or hematopoietic stem-cell transplantation (HSCT) (RR = 3.53; 95% CI = 1.59–7.83).

Conclusion

Although polypharmacy was observed in a minority of included survivors of childhood cancer, chronic medication use was common. Special attention should be paid to survivors of CNS tumors and survivors who have undergone HSCT or cranial radiation. These individuals should be monitored closely for drug–drug interactions and adverse health outcomes that may result from multiple chronic medications, particularly during hospitalization in an acute care setting.
Could We Address the Interplay Between CD133, Wnt/β-Catenin, and TERT Signaling Pathways as a Potential Target for Glioblastoma Therapy?
Authors: Behrooz Amir Barzegar , Syahir Amir
Published: April 2021

Glioblastoma multiforme (GBM) is one of the most lethal forms of primary brain tumors. Glioblastoma stem cells (GSCs) play an undeniable role in tumor development by activating multiple signaling pathways such as Wnt/β-catenin and PI3K/AKT/mTOR that facilitate brain tumor formation. CD133, a transmembrane glycoprotein, has been used to classify cancer stem cells (CSCs) in GBM. The therapeutic value of CD133 is a biomarker of the CSC in multiple cancers. It also leads to growth and recurrence of the tumor. More recent findings have confirmed the association of telomerase/TERT with Wnt/β-catenin and the PI3K/AKT/mTOR signaling pathways. Advance studies have shown that crosstalk between CD133, Wnt/β-catenin, and telomerase/TERT can facilitate GBM stemness and lead to therapeutic resistance. Mechanistic insight into signaling mechanisms downstream of surface biomarkers has been revolutionized by facilitating targeting of tumor-specific molecular deregulation. This review also addresses the importance of interplay between CD133, Wnt/β-catenin and TERT signaling pathways in GSCs and outlines the future therapeutic goals for glioblastoma treatment.
Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy
Authors: Loosen Sven H. , Gorgulho Joao , Jördens Markus S. , Schulze-Hagen Maximilian , Beier Fabian , Vucur Mihael , Schneider Anne T. , Koppe Christiane , Mertens Alexander , Kather Jakob N. , Tacke Frank , Keitel Verena , Brümmendorf Tim H. , Roderburg Christoph , Luedde Tom
Published: April 2021

Background

Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. However, not all patients benefit to the same extend from ICI. Reliable tools to predict treatment response and outcome are missing. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation, whose levels are prognostic in various cancers. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors.

Methods

A total of n = 87 patients receiving ICI therapy for different solid malignancies as well as 32 healthy controls were included into this study. Serum levels of suPAR were measured by ELISA prior to and sequentially at two time points during ICI therapy.

Results

Baseline suPAR serum levels were significantly higher in solid tumor patients compared to healthy controls. Importantly, patients with low suPAR levels both before or during ICI treatment were more likely to have a favorable response to treatment at three and six months, respectively. This finding was confirmed by multivariate binary logistic regression analysis including several clinicopathological parameters. Moreover, circulating suPAR levels before and during therapy were an independent prognostic factor for overall survival (OS). As such, patients with initial suPAR levels above our ideal prognostic cut-off value (4.86 ng/ml) had a median OS of only 160 days compared to 705 days for patients with suPAR levels below this cut-off value. Finally, low baseline suPAR levels identified a subgroup of patients who experienced ICI-related side effects which in turn were associated with favorable treatment response and outcome.

Conclusion

Our data suggest that measurements of suPAR serum levels are a previously unknown, easily accessible tool to predict individual treatment response and outcome to ICI therapy. Circulating suPAR might therefore be implemented into stratification algorithms to identify the ideal candidates for ICI treatment.
Radiosensitization in Pediatric High-Grade Glioma: Targets, Resistance and Developments
Authors: Metselaar Dennis S. , du Chatinier Aimée , Stuiver Iris , Kaspers Gertjan J. L. , Hulleman Esther
Published: April 2021

Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death in children. These epigenetically dysregulated tumors often harbor mutations in genes encoding histone 3, which contributes to a stem cell-like, therapy-resistant phenotype. Furthermore, pHGG are characterized by a diffuse growth pattern, which, together with their delicate location, makes complete surgical resection often impossible. Radiation therapy (RT) is part of the standard therapy against pHGG and generally the only modality, apart from surgery, to provide symptom relief and a delay in tumor progression. However, as a single treatment modality, RT still offers no chance for a cure. As with most therapeutic approaches, irradiated cancer cells often acquire resistance mechanisms that permit survival or stimulate regrowth after treatment, thereby limiting the efficacy of RT. Various preclinical studies have investigated radiosensitizers in pHGG models, without leading to an improved clinical outcome for these patients. However, our recently improved molecular understanding of pHGG generates new opportunities to (re-)evaluate radiosensitizers in these malignancies. Furthermore, the use of radio-enhancing agents has several benefits in pHGG compared to other cancers, which will be discussed here. This review provides an overview and a critical evaluation of the radiosensitization strategies that have been studied to date in pHGG, thereby providing a framework for improving radiosensitivity of these rapidly fatal brain tumors.
Stratified Management for Bacterial Infections in Late Preterm and Term Neonates: Current Strategies and Future Opportunities Toward Precision Medicine
Authors: Keij Fleur M. , Achten Niek B. , Tramper-Stranders Gerdien A. , Allegaert Karel , van Rossum Annemarie M. C. , Reiss Irwin K. M. , Kornelisse René F.
Published: April 2021

Bacterial infections remain a major cause of morbidity and mortality in the neonatal period. Therefore, many neonates, including late preterm and term neonates, are exposed to antibiotics in the first weeks of life. Data on the importance of inter-individual differences and disease signatures are accumulating. Differences that may potentially influence treatment requirement and success rate. However, currently, many neonates are treated following a “one size fits all” approach, based on general protocols and standard antibiotic treatment regimens. Precision medicine has emerged in the last years and is perceived as a new, holistic, way of stratifying patients based on large-scale data including patient characteristics and disease specific features. Specific to sepsis, differences in disease susceptibility, disease severity, immune response and pharmacokinetics and -dynamics can be used for the development of treatment algorithms helping clinicians decide when and how to treat a specific patient or a specific subpopulation. In this review, we highlight the current and future developments that could allow transition to a more precise manner of antibiotic treatment in late preterm and term neonates, and propose a research agenda toward precision medicine for neonatal bacterial infections.
A 3D Copula Method for the Impact and Risk Assessment of Drought Disaster and an Example Application
Authors: Hou Wei , Yan Pengcheng , Feng Guolin , Zuo Dongdong
Published: April 2021

Droughts have more impact on crops than any other natural disaster. Therefore, drought risk assessments, especially quantitative drought risk assessments, are significant in order to understand and reduce the negative impacts associated with droughts, and a quantitative risk assessment includes estimating the probability and consequences of hazards. In order to achieve this goal, we built a model based on the three-dimensional (3D) Copula function for the assessment of the proportion of affected farmland areas (PAFA) based on the idea of internally combining the drought duration, drought intensity, and drought impact. This model achieves the “internal combination” of drought characteristics and drought impacts rather than an “external combination.” The results of this model are not only able to provide the impacts at different levels that a drought event (drought duration and drought intensity) may cause, but are also able to show the occurrence probability of impact at each particular level. We took Huize County and Mengzi County in Yunnan Province as application examples based on the meteorological drought index (SPI), and the results showed that the PAFAs obtained by the method proposed in this paper were basically consistent with the actual PAFAs in the two counties. Moreover, due to the meteorological drought always occurring before an agricultural drought, we can get SPI predictions for the next month or months and can further obtain more abundant information on a drought warning and its impact. Therefore, the method proposed in this paper has values both on theory and practice.
Electron and Ion Transport of Tin Dioxide in Secondary Batteries: Enhancement Approaches, Mechanisms, and Performance
Authors: Han Tianli , Qi Mingqiang , Yang Shanshan , Diao Xinya , Long Jiawei , Zhu Mengfei , Xu Xiaoyong , Hu Chaoquan , Liu Jinyun
Published: April 2021

Secondary batteries have been important across several aspects of daily life and industrial manufacture. The electron and ion transport of electrodes significantly affects the energy-storage performance of batteries. Among many fascinating materials, transition metal oxides have been considered promising as candidate electrode materials of high-performance batteries owing to their high theoretical capacity and good stability. Herein, tin dioxide is chosen as a representative transition metal oxide to show the specific electron and ion transport in some types of secondary batteries including lithium-ion, lithium-sulfur, potassium-ion batteries, etc. The way to optimize the structure and the strategies to enhance electron and ion transport have been summarized. Recently, tin dioxide doping and the preparation of tin dioxide-based composites have been reported. In addition, the main challenges and possible prospects are also proposed, which provide important suggestions for researchers to develop high-performance energy-storage materials and to explore new physical science.
The Association Between Notching of the Right Ventricular Outflow Tract Flow Velocity Doppler Envelope and Impaired Right Ventricular Function After Acute High-Altitude Exposure
Authors: Yuan Fangzhengyuan , Liu Chuan , Yu Shiyong , Bian Shizhu , Yang Jie , Ding Xiaohan , Zhang Jihang , Tan Hu , Ke Jingbin , Yang Yuanqi , He Chunyan , Zhang Chen , Rao Rongsheng , Liu Zhaojun , Yang Jun , Huang Lan
Published: April 2021

Introduction

Pulmonary artery pressure (PAP) is increased and right ventricular (RV) function is well preserved in healthy subjects upon exposure to high altitude (HA). An increase in PAP may trigger notching of the right ventricular outflow tract Doppler flow velocity envelope (RVOT notch), which is associated with impaired RV function in patients with pulmonary hypertension. However, whether HA exposure can induce RVOT notch formation and the subsequent impact on cardiac function in healthy subjects remains unclear.

Methods

A total of 99 subjects (69 males and 30 females) with a median age of 25 years were enrolled in this study; they traveled from 500 to 4100 m by bus over a 2-day period. All subjects underwent a comprehensive physiological and echocardiographic examination 1 day before ascension at low altitude and 15 ± 3 h after arrival at HA. The RVOT notch was determined by the presence of a notched shape in the RVOT Doppler flow velocity envelope. The systolic PAP (SPAP) was calculated as Bernoulli equation SPAP = 4 × (maximum tricuspid regurgitation velocity)2+5 and mean PAP (mPAP) = 0.61 × SPAP+2. Cardiac output was calculated as stroke volume × heart rate. Pulmonary capillary wedge pressure (PCWP) was calculated as 1.9+1.24 × mitral E/e’. Pulmonary vascular resistance (PVR) was calculated as (mPAP-PCWP)/CO.

Results

After HA exposure, 20 (20.2%) subjects had an RVOT notch [notch (+)], and 79 (79.8%) subjects did not have an RVOT notch [notch (−)]. In the multivariate logistic regression analysis, the SPAP, right ventricular global longitude strain (RV GLS), and tricuspid E/A were independently associated with the RVOT notch. The SPAP, mPAP, PVR, standard deviations of the times to peak systolic strain in the four mid-basal RV segments (RVSD4), peak velocity of the isovolumic contraction period (ICV), and the peak systolic velocity (s’) at the mitral/tricuspid annulus were increased in all subjects. Conversely, the pulse oxygen saturation (SpO2), RV GLS, and tricuspid annulus plane systolic excursion (TAPSE)/SPAP were decreased. However, the increases of SPAP, mPAP, PVR, and RVSD4 and the decreases of SpO2, RV GLS, and TAPSE/SPAP were more pronounced in the notch (+) group than in the notch (−) group. Additionally, increased tricuspid ICV and mitral/tricuspid s’ were found only in the notch (−) group.

Conclusion

HA exposure-induced RVOT notch formation is associated with impaired RV function, including no increase in the tricuspid ICV or s’, reduction of RV deformation, deterioration in RV-pulmonary artery coupling, and RV intraventricular synchrony.
Identification and Functional Analysis of Long Non-coding RNAs in Human Pulmonary Microvascular Endothelial Cells Subjected to Cyclic Stretch
Authors: Wang Dong , Dai Chenyang , Zhang Xiaoning , Gu Changping , Liu Mengjie , Liu Huan , Yang Fan , Wu Haifeng , Wang Yuelan
Published: April 2021

Background: Despite decades of intense research, the pathophysiology and pathogenesis of acute respiratory distress syndrome (ARDS) are not adequately elucidated, which hamper the improvement of effective and convincing therapies for ARDS patients. Mechanical ventilation remains to be one of the primary supportive approaches for managing ARDS cases. Nevertheless, mechanical ventilation leads to the induction of further aggravating lung injury which is known as leading to ventilator-induced lung injury (VILI). It has been reported that lncRNAs play important roles in various cellular process through transcriptional, posttranscriptional, translational, and epigenetic regulations. However, to our knowledge, there is no investigation of the expression profile and functions of transcriptome-level endothelium-related lncRNAs in VILI yet.

Methods: To screen the differential expression of lncRNAs and mRNAs in Human pulmonary microvascular endothelial cells (HPMECs) subjected to cyclic stretch, we constructed a cellular model of VILI, followed by transcriptome profiling using Affymetrix Human Transcriptome Array 2.0. Bioinformatics analyses, including functional and pathway enrichment analysis, protein–protein interaction network, lncRNA-mRNA coexpression network, and cis-analyses, were performed to reveal the potential functions and underlying mechanisms of differentially expressed lncRNAs.

Results: In total, 199 differentially expressed lncRNAs (DELs) and 97 differential expressed mRNAs were screened in HPMECs subjected to 20% cyclic stretch for 2 h. The lncRNA-mRNA coexpression network suggested that DELs mainly enriched in response to hypoxia, response to oxidative stress, inflammatory response, cellular response to hypoxia, and NF-kappa B signaling pathway. LncRNA n335470, n406639, n333984, and n337322 might regulate inflammation and fibrosis induced by cyclic stretch through cis- or trans-acting mechanisms.

Conclusion: This study provides the first transcriptomic landscape of differentially expressed lncRNAs in HPMECs subjected to cyclic stretch, which provides novel insights into the molecular mechanisms and potential directions for future basic and clinical research of VILI.