bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic Regulations of Perineural Invasion in Head and Neck Squamous Cell Carcinoma
Authors: Hurník Pavel , Chyra Zuzana , Ševčíková Tereza , Štembírek Jan , Trtková Kateřina Smešný , Gaykalova Daria A. , Buchtová Marcela , Hrubá Eva
Published: April 2022

Carcinomas of the oral cavity and oropharynx belong among the ten most common malignancies in the human population. The prognosis of head and neck squamous cell carcinoma (HNSCC) is determined by the degree of invasiveness of the primary tumor and by the extent of metastatic spread into regional and distant lymph nodes. Moreover, the level of the perineural invasion itself associates with tumor localization, invasion’s extent, and the presence of nodal metastases. Here, we summarize the current knowledge about different aspects of epigenetic changes, which can be associated with HNSCC while focusing on perineural invasion (PNI). We review epigenetic modifications of the genes involved in the PNI process in HNSCC from the omics perspective and specific epigenetic modifications in OSCC or other neurotropic cancers associated with perineural invasion. Moreover, we summarize DNA methylation status of tumor-suppressor genes, methylation and demethylation enzymes and histone post-translational modifications associated with PNI. The influence of other epigenetic factors on the HNSCC incidence and perineural invasion such as tobacco, alcohol and oral microbiome is overviewed and HPV infection is discussed as an epigenetic factor associated with OSCC and related perineural invasion. Understanding epigenetic regulations of axon growth that lead to tumorous spread or uncovering the molecular control of axon interaction with cancer tissue can help to discover new therapeutic targets for these tumors.
Genome Instability-Associated Long Non-Coding RNAs Reveal Biomarkers for Glioma Immunotherapy and Prognosis
Authors: Wang Xinzhuang , Zhang Hong , Ye Junyi , Gao Ming , Jiang Qiuyi , Zhao Tingting , Wang Shengtao , Mao Wenbin , Wang Kaili , Wang Qi , Chen Xin , Hou Xu , Han Dayong
Published: April 2022

Genome instability is a hallmark of tumors and is involved in proliferation, invasion, migration, and treatment resistance of many tumors. However, the relationship of genome instability with gliomas remains unclear. Here, we constructed genome instability-derived long non-coding RNA (lncRNA)-based gene signatures (GILncSig) using genome instability-related lncRNAs derived from somatic mutations. Multiple platforms were used to confirm that the GILncSig were closely related to patient prognosis and clinical characteristics. We found that GILncSig, the glioma microenvironment, and glioma cell DNA methylation-based stemness index (mDNAsi) interacted with each other to form a complex regulatory network. In summary, this study confirmed that GILncSig was an independent prognostic indicator for patients, distinguished high-risk and low-risk groups, and affected immune-cell infiltration and tumor-cell stemness indicators (mDNAsi) in the tumor microenvironment, resulting in tumor heterogeneity and immunotherapy resistance. GILncSig are expected to provide new molecular targets for the clinical treatment of patients with gliomas.
Refined Contact Map Prediction of Peptides Based on GCN and ResNet
Authors: Gu Jiawei , Zhang Tianhao , Wu Chunguo , Liang Yanchun , Shi Xiaohu
Published: April 2022

Predicting peptide inter-residue contact maps plays an important role in computational biology, which determines the topology of the peptide structure. However, due to the limited number of known homologous structures, there is still much room for inter-residue contact map prediction. Current models are not sufficient for capturing the high accuracy relationship between the residues, especially for those with a long-range distance. In this article, we developed a novel deep neural network framework to refine the rough contact map produced by the existing methods. The rough contact map is used to construct the residue graph that is processed by the graph convolutional neural network (GCN). GCN can better capture the global information and is therefore used to grasp the long-range contact relationship. The residual convolutional neural network is also applied in the framework for learning local information. We conducted the experiments on four different test datasets, and the inter-residue long-range contact map prediction accuracy demonstrates the effectiveness of our proposed method.
Identification of Novel Prognostic Biomarkers Relevant to Immune Infiltration in Lung Adenocarcinoma
Authors: Xia Zhi , Rong Xueyao , Dai Ziyu , Zhou Dongbo
Published: April 2022

Background: Programmed death ligand-1 (PD-L1) is a biomarker for assessing the immune microenvironment, prognosis, and response to immune checkpoint inhibitors in the clinical treatment of lung adenocarcinoma (LUAD), but it does not work for all patients. This study aims to discover alternative biomarkers.

Methods: Public data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) were used to determine the gene modules relevant to tumor immunity. Protein–protein interaction (PPI) network and GO semantic similarity analyses were applied to identify the module hub genes with functional similarities to PD-L1, and we assessed their correlations with immune infiltration, patient prognosis, and immunotherapy response. Immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining were used to validate the outcome at the protein level.

Results: We identified an immune response–related module, and two hub genes (PSTPIP1 and PILRA) were selected as potential biomarkers with functional similarities to PD-L1. High expression levels of PSTPIP1 and PILRA were associated with longer overall survival and rich immune infiltration in LUAD patients, and both were significantly high in patients who responded to anti–PD-L1 treatment. Compared to PD-L1–negative LUAD tissues, the protein levels of PSTPIP1 and PILRA were relatively increased in the PD-L1–positive tissues, and the expression of PSTPIP1 and PILRA positively correlated with the tumor-infiltrating lymphocytes.

Conclusion: We identified PSTPIP1 and PILRA as prognostic biomarkers relevant to immune infiltration in LUAD, and both are associated with the response to anti–PD-L1 treatment.
Incomplete Penetrance of Population-Based Genetic Screening Results in Electronic Health Record
Authors: Elhanan Gai , Kiser Daniel , Neveux Iva , Dabe Shaun , Bolze Alexandre , Metcalf William J. , Lu James T. , Grzymski Joseph J.
Published: April 2022

The clinical value of population-based genetic screening projects depends on the actions taken on the findings. The Healthy Nevada Project (HNP) is an all-comer genetic screening and research project based in northern Nevada. HNP participants with CDC Tier 1 findings of hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), or familial hypercholesterolemia (FH) are notified and provided with genetic counseling. However, the HNP subsequently takes a “hands-off” approach: it is the responsibility of notified participants to share their findings with their healthcare providers, and providers are expected to implement the recommended action plans. Thus, the HNP presents an opportunity to evaluate the efficiency of participant and provider responses to notification of important genetic findings, using electronic health records (EHRs) at Renown Health (a large regional hospital in northern Nevada). Out of 520 HNP participants with findings, we identified 250 participants who were notified of their findings and who had an EHR. 107 of these participants responded to a survey, with 76 (71%) indicating that they had shared their findings with their healthcare providers. However, a sufficiently specific genetic diagnosis appeared in the EHRs and problem lists of only 22 and 10%, respectively, of participants without prior knowledge. Furthermore, review of participant EHRs provided evidence of possible relevant changes in clinical care for only a handful of participants. Up to 19% of participants would have benefited from earlier screening due to prior presentation of their condition. These results suggest that continuous support for both participants and their providers is necessary to maximize the benefit of population-based genetic screening. We recommend that genetic screening projects require participants’ consent to directly document their genetic findings in their EHRs. Additionally, we recommend that they provide healthcare providers with ongoing training regarding documentation of findings and with clinical decision support regarding subsequent care.
Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy
Authors: Chuan Zhang , Ruikun Cai , Qian Li , Shiyue Mei , Shengju Hao , Yong Yuan , Haibo Li , Neng Xiao , Yong Zhao , Huiqin Xue , Weijia Wang , Ling Hui , Bingbo Zhou , Zhang Qinghua , Yan Wang , Zongfu Cao , Xu Ma
Published: April 2022

Background:Epilepsy in childhood is a common and diverse neurological disorder. We conducted a genetic and phenotype analysis of a Chinese cohort of infants and children with epilepsy.

Methods:We conducted a pedigree analysis of 260 Chinese patients with epilepsy onset during infancy or childhood by whole exome sequencing (WES).

Results:Of the 260 probands analyzed, a genetic diagnosis was established in 135 patients. One-hundred eighty-eight phenotypes were detected in those 135 positive/likely positive patients, 106 patients had more than two phenotypes, and 67 patients had more than three phenotypes. A total of 142 variants of 81 genes were detected among the positive/likely positive patients. Among these 142 variants, of which 87 of 66 genes were novel.

Conclusion:Our findings extend the variant spectrum of genes related to epilepsy. Our results will be useful for genetic testing and counseling for patients with epilepsy.
Trans-Renal Cell-Free Tumor DNA for Urine-Based Liquid Biopsy of Cancer
Authors: Dermody Sarah M. , Bhambhani Chandan , Swiecicki Paul L. , Brenner J. Chad , Tewari Muneesh
Published: April 2022

Cancer biomarkers are a promising tool for cancer detection, personalization of therapy, and monitoring of treatment response or recurrence. “Liquid biopsy” commonly refers to minimally invasive or non-invasive sampling of a bodily fluid (i.e., blood, urine, saliva) for detection of cancer biomarkers such as circulating tumor cells or cell-free tumor DNA (ctDNA). These methods offer a means to collect frequent tumor assessments without needing surgical biopsies. Despite much progress with blood-based liquid biopsy approaches, there are limitations—including the limited amount of blood that can be drawn from a person and challenges with collecting blood samples at frequent intervals to capture ctDNA biomarker kinetics. These limitations are important because ctDNA is present at extremely low levels in plasma and there is evidence that measuring ctDNA biomarker kinetics over time can be useful for clinical prediction. Additionally, blood-based assays require access to trained phlebotomists and often a trip to a healthcare facility. In contrast, urine is a body fluid that can be self-collected from a patient’s home, at frequent intervals, and mailed to a laboratory for analysis. Multiple reports indicate that fragments of ctDNA pass from the bloodstream through the kidney’s glomerular filtration system into the urine, where they are known as trans-renal ctDNA (TR-ctDNA). Accumulating studies indicate that the limitations of blood based ctDNA approaches for cancer can be overcome by measuring TR-ctDNA. Here, we review current knowledge about TR-ctDNA in urine as a cancer biomarker approach, and discuss its clinical potential and open questions in this research field.
i2APP: A Two-Step Machine Learning Framework For Antiparasitic Peptides Identification
Authors: Jiang Minchao , Zhang Renfeng , Xia Yixiao , Jia Gangyong , Yin Yuyu , Wang Pu , Wu Jian , Ge Ruiquan
Published: April 2022

Parasites can cause enormous damage to their hosts. Studies have shown that antiparasitic peptides can inhibit the growth and development of parasites and even kill them. Because traditional biological methods to determine the activity of antiparasitic peptides are time-consuming and costly, a method for large-scale prediction of antiparasitic peptides is urgently needed. We propose a computational approach called i2APP that can efficiently identify APPs using a two-step machine learning (ML) framework. First, in order to solve the imbalance of positive and negative samples in the training set, a random under sampling method is used to generate a balanced training data set. Then, the physical and chemical features and terminus-based features are extracted, and the first classification is performed by Light Gradient Boosting Machine (LGBM) and Support Vector Machine (SVM) to obtain 264-dimensional higher level features. These features are selected by Maximal Information Coefficient (MIC) and the features with the big MIC values are retained. Finally, the SVM algorithm is used for the second classification in the optimized feature space. Thus the prediction model i2APP is fully constructed. On independent datasets, the accuracy and AUC of i2APP are 0.913 and 0.935, respectively, which are better than the state-of-arts methods. The key idea of the proposed method is that multi-level features are extracted from peptide sequences and the higher-level features can distinguish well the APPs and non-APPs.
Pan-Cancer Bioinformatics Analysis of Gene UBE2C
Authors: Yuan Lin , Yang Zhenyu , Zhao Jing , Sun Tao , Hu Chunyu , Shen Zhen , Yu Guanying
Published: April 2022

Ubiquitin-Conjugating Enzyme E2 C (UBE2C) is a gene that encodes protein. Disorders associated with UBE2C include methotrexate-related lymphatic hyperplasia and complement component 7 deficiency. The encoded protein is necessary for the destruction of mitotic cell cyclins and cell cycle progression, and may be involved in cancer progression. In this paper, on the basis of public databases, we study the expression differential mechanism of gene expression of UBE2C in various tumors and the performance of prognosis, clinical features, immunity, methylation, etc.
Sulfadiazine Plus Pyrimethamine Therapy Reversed Multiple Behavioral and Neurocognitive Changes in Long-Term Chronic Toxoplasmosis by Reducing Brain Cyst Load and Inflammation-Related Alterations
Authors: Castaño Barrios Leda , Silva Andrea Alice , Hernandez-Velasco Lina L , Pinheiro Ana Paula Da Silva , Gibaldi Daniel , Mineo José Roberto , Silva Neide Maria , Lannes-Vieira Joseli
Published: April 2022

Toxoplasma gondiiinfects one-third of the world population. For decades, it has been considered a silent lifelong infection. However, chronicallyT. gondii-infected persons may present psychiatric and neurocognitive changes as anxiety, depression, and memory loss. In a model of long-term chronic infection, behavioral alterations parallel neuroinflammation and systemic high cytokine levels, and may reflect brain cyst load. Recent findings support that in chronic infection an active parasite-host interplay involves an immune-mediated control of tissue cysts. Here, we tested the idea that etiological treatment in chronic phase may add advantage to intrinsic immune-mediated cyst control and impact behavioral changes. Thus, we combined sulfadiazine-plus-pyrimethamine (S+P), the first-choice therapy for toxoplasmosis, to study the association of brain cyst load and biological processes related to the immune response (neuroinflammation, blood-brain barrier -BBB- disruption and serum cytokine levels), with behavioral and neurocognitive changes of long-term chronic infection. Female C57BL/6 mice (H-2b) were infected (5 cysts, ME-49 strain) and treated with S+P from 30 to 60 days postinfection (dpi), compared with vehicle (Veh)-treated and noninfected controls. At endpoints (pre-therapy, 30 dpi; S+P therapy, 60 dpi; after ceased therapy, 90 dpi), independent groups were subjected to behavioral tests, and brain tissues and sera were collected. Multiple behavioral and neurocognitive changes were detected in the early (30 dpi) and long-term (60 and 90 dpi) chronic infection. S+P therapy resolved locomotor alterations, anxiety, and depressive-like behavior, partially or transiently ameliorated hyperactivity and habituation memory loss. Analysis after therapy cessation showed that S+P therapy reduced the number of stimuli required for aversive memory consolidation. S+P therapy resulted in reduced brain cyst load, neuroinflammation and BBB disruption, and lowered systemic Th1-cytokine levels. Correlation analysis revealed association between IFNγ, TNF and MCP-1/CCL2 serum levels, brain cyst load and behavioral and neurocognitive alterations. Moreover, principal-component analysis (PCA-2D and 3D projections) highlighted distinction between clusters (noninfected; Veh-treated and S+P-treated infected). Thus, our data suggest that S+P therapy added gain to intrinsic brain cyst control and, direct or indirectly, ameliorated inflammation-related alterations, traits associated with behavioral and neurocognitive alterations.
Vaccines for COVID-19: A Systematic Review of Immunogenicity, Current Development, and Future Prospects
Authors: Zhang Zhan , Shen Qi , Chang Haocai
Published: April 2022

The persistent coronavirus disease 2019 (COVID-19), characterized by severe respiratory syndrome, is caused by coronavirus 2 (SARS-CoV-2), and it poses a major threat to public health all over the world. Currently, optimal COVID-19 management involves effective vaccination. Vaccination is known to greatly enhance immune response against viral infections and reduce public transmission of COVID-19. However, although current vaccines offer some benefits, viral variations and other factors demand the continuous development of vaccines to eliminate this virus from host. Hence, vaccine research and development is crucial and urgent to the elimination of this pandemic. Herein, we summarized the structural and replicatory features of SARS-CoV-2, and focused on vaccine-mediated disease prevention strategies like vaccine antigen selection, vaccine research, and vaccine application. We also evaluated the latest literature on COVID-19 and extensively reviewed action mechanisms, clinical trial (CT) progresses, advantages, as well as disadvantages of various vaccine candidates against SARS-CoV-2. Lastly, we discussed the current viral treatment, prevention trends, and future prospects.
Microvesicle-Mediated Communication Within the Alveolar Space: Mechanisms of Uptake by Epithelial Cells and Alveolar Macrophages
Authors: Soni Sanooj , O’Dea Kieran P. , Abe Eiko , Khamdan Maryam , Shah Sneh V. , Sarathchandra Padmini , Wilson Michael R. , Takata Masao
Published: April 2022

Intra-alveolar microvesicles (MVs) are important mediators of inter-cellular communication within the alveolar space, and are key components in the pathophysiology of lung inflammation such as acute respiratory distress syndrome (ARDS). Despite the abundance of data detailing the pro-inflammatory effects of MVs, it remains unclear how MVs interact or signal with target cells in the alveolus. Using both in vivo and in vitro alveolar models, we analyzed the dynamics of MV uptake by resident alveolar cells: alveolar macrophages and epithelial cells. Under resting conditions, the overwhelming majority of MVs were taken up by alveolar macrophages. However, following lipopolysaccharide (LPS)-mediated inflammation, epithelial cells internalized significantly more MVs (p<0.01) whilst alveolar macrophage internalization was significantly reduced (p<0.01). We found that alveolar macrophages adopted a pro-inflammatory phenotype after internalizing MVs under resting conditions, but reduction of MV uptake following LPS pre-treatment was associated with loss of inflammatory phenotype. Instead, MVs induced significant epithelial cell inflammation following LPS pre-treatment, when MV internalization was most significant. Using pharmacological inhibitors, we interrogated the mechanisms of MV internalization to identify which endocytic pathways and cell surface receptors are involved. We demonstrated that epithelial cells are exclusively dependent on the clathrin and caveolin dependent endocytotic pathway, whereas alveolar macrophage uptake may involve a significant phagocytic component. Furthermore, alveolar macrophages predominantly engulf MVs via scavenger receptors whilst, epithelial cells internalize MVs via a phosphatidylserine/integrin receptor mediated pathway (specifically alpha V beta III), which can be inhibited with phosphatidylserine-binding protein (i.e. annexin V). In summary, we have undertaken a comprehensive evaluation of MV internalization within the alveolar space. Our results demonstrate that different environmental conditions can modulate MV internalization, with inflammatory stimuli strongly enhancing epithelial cell uptake of MVs and inducing epithelial cell activation. Our data reveal the unique mechanisms by which alveolar macrophages and epithelial cells internalize MVs thereby elucidating how MVs exert their pathophysiological effect during lung inflammation and injury. As MVs are potential novel therapeutic targets in conditions such as ARDS, these data provide crucial insights into the dynamics of MV-target cell interactions and highlight potential avenues for researchers to modulate and inhibit their pro-inflammatory actions within the alveolar space.
A Novel miRNA From Egg-Derived Exosomes of Schistosoma japonicum Promotes Liver Fibrosis in Murine Schistosomiasis
Authors: Wang Yiluo , Gong Wenci , Zhou Hao , Hu Yuan , Wang Lan , Shen Yujuan , Yu Guoying , Cao Jianping
Published: April 2022

Schistosomiasis caused by Schistosoma japonicum is a serious public health problem in China. Granuloma and hepatic fibrosis are the main pathological features of schistosomiasis japonica. The role and mechanism of egg-derived exosomes of S. japonicum in liver fibrosis remain unclear. In this study, we found that egg-derived exosomes of S. japonicum carry a new type of microRNA (miRNA-33). In vitro, this novel miRNA upregulated the expression of smooth muscle actin (α-SMA) and collagen 1 α1 (Col 1 α1) in the human hepatic stellate cell (LX-2) line at both mRNA and protein levels. In vivo, this novel miRNA was upregulated in the serum of infected mice, and when injected into mice through the tail vein using miRNA agomir, α-SMA, Col 1 α1, and Col 3 α1 were upregulated in liver tissue at both mRNA and protein levels. In addition, this novel miRNA downregulated the expression of α-SMA and Col 1 α1 in liver tissue at mRNA and protein levels in mice infected with S. japonicum and treated with miRNA antagomir. The novel miRNA-33 upregulated TGF-β Receptor I (TGF-β RI) at both mRNA and protein levels in LX-2 cells. Our results suggest that this novel miRNA from egg-derived exosomes of S. japonicum can promote liver fibrosis in the host in a cross-species manner, and the degree of fibrosis can be decreased by inhibiting the expression of this miRNA.
Inborn Errors of the Immune System Associated With Atopy
Authors: Nelson Ryan W. , Geha Raif S. , McDonald Douglas R.
Published: April 2022

Atopic disorders, including atopic dermatitis, food and environmental allergies, and asthma, are increasingly prevalent diseases. Atopic disorders are often associated with eosinophilia, driven by T helper type 2 (Th2) immune responses, and triggered by disrupted barrier function leading to abnormal immune priming in a susceptible host. Immune deficiencies, in contrast, occur with a significantly lower incidence, but are associated with greater morbidity and mortality. A subset of atopic disorders with eosinophilia and elevated IgE are associated with monogenic inborn errors of immunity (IEI). In this review, we discuss current knowledge of IEI that are associated with atopy and the lessons these immunologic disorders provide regarding the fundamental mechanisms that regulate type 2 immunity in humans. We also discuss further mechanistic insights provided by animal models.
Monosodium Glutamate-Induced Mouse Model With Unique Diabetic Retinal Neuropathy Features and Artificial Intelligence Techniques for Quantitative Evaluation
Authors: Liu Yanfei , Huang Hui , Sun Yu , Li Yiwen , Luo Binyu , Cui Jing , Zhu Mengmeng , Bi Fukun , Chen Keji , Liu Yue
Published: April 2022

Objective

To establish an artificial intelligence-based method to quantitatively evaluate subtle pathological changes in retinal nerve cells and synapses in monosodium glutamate (MSG) mice and provide an effective animal model and technique for quantitative evaluation of retinal neurocytopathies.

Methods

ICR mice were subcutaneously injected with MSG to establish a model of metabolic syndrome. We then established a mouse model of type 1 diabetes, type 2 diabetes, and KKAy mouse model as control. The HE sections of the retina were visualized using an optical microscope. AI technology was used for quantitative evaluation of the retinal lesions in each group of rats. The surface area custom parameters of the retinal nerve fiber layer (RNFL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL) were defined as SR, SIPL, SINL, and SOPL, respectively. Their heights were defined as HR, HIPL, HINL, and HOPL, and the number of ganglion cells was defined as A. Then, the attention-augmented fully convolutional Unet network was used to segment the retinal HE images, and AI technology to identify retinal neurocytopathies quantitatively.

Results

The attention-augmented fully convolutional Unet network increased PA and IOU parameters for INL, OPL, RNFL, and ganglion cells and was superior in recognizing fine structures. A quantitative AI identification of the height of each layer of the retina showed that the heights of the IPL and INL of the MSG model were significantly less than those of the control groups; the retinas of the other diabetic models did not exhibit this pathological feature. The RNFLs of type 2 diabetes were thinner, and the characteristics of retinopathy were not obvious in the other animal models. The pathological changes seen on HE images were consistent with the results of the quantitative AI evaluation. Immunohistochemistry results showed that NMDAR2A, GluR2, and NRG1 were significantly downregulated in the retina of MSG mice.

Conclusions

The MSG retinopathy model is closely associated with neurotransmitter abnormalities and exhibits important characteristics of retinal neurodegeneration, making it suitable for studying retinal neurocytopathies. The AI recognition technology for retinal images established in the present study can be used for the quantitative and objective evaluation of drug efficacy.
Multiple-Allele MHC Class II Epitope Engineering by a Molecular Dynamics-Based Evolution Protocol
Authors: Ochoa Rodrigo , Lunardelli Victoria Alves Santos , Rosa Daniela Santoro , Laio Alessandro , Cossio Pilar
Published: April 2022

Epitopes that bind simultaneously to all human alleles of Major Histocompatibility Complex class II (MHC II) are considered one of the key factors for the development of improved vaccines and cancer immunotherapies. To engineer MHC II multiple-allele binders, we developed a protocol called PanMHC-PARCE, based on the unsupervised optimization of the epitope sequence by single-point mutations, parallel explicit-solvent molecular dynamics simulations and scoring of the MHC II-epitope complexes. The key idea is accepting mutations that not only improve the affinity but also reduce the affinity gap between the alleles. We applied this methodology to enhance a Plasmodium vivax epitope for multiple-allele binding. In vitro rate-binding assays showed that four engineered peptides were able to bind with improved affinity toward multiple human MHC II alleles. Moreover, we demonstrated that mice immunized with the peptides exhibited interferon-gamma cellular immune response. Overall, the method enables the engineering of peptides with improved binding properties that can be used for the generation of new immunotherapies.
Identification of Implications of Angiogenesis and m6A Modification on Immunosuppression and Therapeutic Sensitivity in Low-Grade Glioma by Network Computational Analysis of Subtypes and Signatures
Authors: Li Bo , Wang Fang , Wang Nan , Hou Kuiyuan , Du Jianyang
Published: April 2022

Angiogenesis is a complex process in the immunosuppressed low-grade gliomas (LGG) microenvironment and is regulated by multiple factors. N6-methyladenosine (m6A), modified by the m6A modification regulators (“writers” “readers” and “erasers”), can drive LGG formation. In the hypoxic environment of intracranial tumor immune microenvironment (TIME), m6A modifications in glioma stem cells are predominantly distributed around neovascularization and synergize with complex perivascular pathological ecology to mediate the immunosuppressive phenotype of TIME. The exact mechanism of this phenomenon remains unknown. Herein, we elucidated the relevance of the angiogenesis-related genes (ARGs) and m6A regulators (MAGs) and their influencing mechanism from a macro perspective. Based on the expression pattern of MAGs, we divided patients with LGG into two robust categories via consensus clustering, and further annotated the malignant related mechanisms and corresponding targeted agents. The two subgroups (CL1, CL2) demonstrated a significant correlation with prognosis and clinical-pathology features. Moreover, WGCNA has also uncovered the hub genes and related mechanisms of MAGs affecting clinical characters. Clustering analysis revealed a synergistic promoting effect of M6A and angiogenesis on immunosuppression. Based on the expression patterns of MAGs, we established a high-performance gene-signature (MASig). MASig revealed somatic mutational mechanisms by which MAGs affect the sensitivity to treatment in LGG patients. In conclusion, the MAGs were critical participants in the malignant process of LGG, with a vital potential in the prognosis stratification, prediction of outcome, and therapeutic sensitivity of LGG. Findings based on these strategies may facilitate the development of objective diagnosis and treatment systems to quantify patient survival and other outcomes, and in some cases, to identify potential unexplored targeted therapies.
Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells
Authors: Wang Qianqian , Huang Chao , Ding Ying , Wen Shaodi , Wang Xin , Guo Shuwei , Gao Qiuzhi , Chen Zhihong , Zhao Yuanyuan , Wang Mei , Shen Bo , Zhu Wei
Published: April 2022

Background

Gastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in the development of therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between cancer and immune cells has been well studied. Emerging evidence suggests that PD-L1 also contributes to tumor resistance to therapy.

Methods

Cell survival and apoptosis were assessed using CCK-8, colony formation, and flow cytometry assays. Protein alterations were analyzed via Western blot. Gene knockdown and overexpression were achieved with siRNA/shRNA and lentiviral infection, respectively. Drug effects on tumors in vivo were assessed with xenografts in nude mice. In addition, GC patient samples after chemotherapy treatment were collected to observe the relationship between chemotherapy effect and CTCF or PD-L1.

Results

In response to 5-fluorouracil or paclitaxel treatment, GCMSC-CM enhanced the cell viability and decreased the apoptosis rate. Furthermore, blocking PD-L1 or CTCF in GC cells prevented GCMSC-induced drug resistance accompanied by a decline in cell stemness. Consistent with these in vitro observations, mice treated with GCMSC-CM showed a lower sensitivity to 5-fluorouracil. In addition, high expression of CTCF and PD-L1 was associated with poor chemotherapy progression in the clinic.

Conclusion

Study results demonstrate a mechanism where GCMSC-CM promotes GC chemoresistance by upregulating CTCF-PD-L1 and provide strong evidence in support of targeting CTCF-PD-L1 signaling as a strategy to prevent resistance in the clinic.
Effect of Polypropylene Grafted Maleic Anhydride (PP-G-MAH) on the Properties of Asphalt and its Mixture Modified With Recycled Polyethylene/Recycled Polypropylene (RPE/RPP) Blends
Authors: Zhang Wencai , Hao Xiaogang , Fan Changxin , Zhang Shuai , Ma Dechong , Yu Xiaofang , Fu Zhaohua , Feng Gongji
Published: April 2022

In this study, a ternary blend modifier (TBM) was prepared with RPE, RPP, and various dosages of PP-g-MAH (i.e., 0%, 1%, 3%, 5%, 7%, and 9% by weight of RPE and RPP) by a twin-screw extruder. The performance of TBM (4% by weight of asphalt) modified asphalt was studied, with the increase of PP-g-MAH content, the penetration decreases gradually, but softening point and viscosity increases and ductility exists minimum value at 7% content, with the increasing of PP-g-MAH percentage, the dynamic rheological properties show that |G*| increases, while the δ and |G*|cosδ decrease, and the fatigue performance (|G*|sinδ) of TBM modified asphalt is worse than virgin asphalt. Dynamic stability test shows that TBM shows the prominent high-temperature properties of a modified (asphalt mixture. BBR test indicates that the m-value of asphalt modified with TBM does not fulfill the requirements (m-value>0.3) except at 5% and 7%, but the S meets the standard requirements (S < 300 MPa), and increases from 0% to 7%, then decreases slightly. In order to illuminate possible reasons, a chemical reaction (ester compounds generated) and physical twines of concerned polymer molecules were put forward, and the results were confirmed by infrared analysis.
Formation and Effect of Deposited Thin TiO2 Layer With Compressive Strain and Oxygen Vacancies on GaAs (001) Substrate
Authors: Li Yue , Zhou Yunxia , Deng Yanrong , Ta Shiwo , Yang Zhao , Li Haiou , Sun Tangyou , Chen Yonghe , Zhang Fabi , Fu Tao , Wangyang Peihua , Zhu Jun , Zeng Lizhen , Liu Xingpeng
Published: April 2022

The integration of metal oxides and GaAs semiconductors is quite attractive for its potential applications, but interfacial diffusion and lattice mismatch usually cause huge challenges toward achieving high-performance electronic devices. In this article, we reported a thin layer of epitaxial TiO2 (110) on a GaAs (001) substrate with significant compressive strain, lattice distortion, and oxygen vacancies, where the oxygen vacancies proved to be the critical factor to induce the compressive strain and lattice distortion. In this case, the lattice mismatches between this compressed TiO2 (110) and GaAs (001) surface were calculated to be as small as 1.3 and 0.24% along the [110] and [001] orientations of TiO2, respectively. Further, no Ga-oxides or As-oxides were found at the interface, indicating that the TiO2 layer inhibited the diffusion of Ga and As atoms effectively. In summary, TiO2 film can be grown epitaxially on GaAs (001) substrates with non-negligible compressive strain, lattice distortion, oxygen vacancies, and a high-quality interface. This study also provides an approach to integrate different functional oxides on TiO2-buffered GaAs for various GaAs-based electronic devices with higher reliability and performance.
Effect of Different Environmental Conditions on Durabilities of Polyester- and Vinylester-Based Glass-Fiber-Reinforced Polymer Pultruded Profiles
Authors: Yang Shulan , Chu Mingkun , Chen Fangyi , Fu Miaorui , Lv Yiwen , Xiao Ziyi , Feng Ningning , Song Yang , Li Jiannan
Published: April 2022

This paper presents the results of experimental investigations on the durability of glass-fiber-reinforced polymer (GFRP) pultruded profiles made of unsaturated polyester (UP) and vinylester (VE) resins commonly used in civil engineering. The water absorption, tensile properties, and microstructures of GFRP profiles exposed to several typical accelerated aging environments (e.g., deionized water, salt water, salt fog, and combined hygrothermal cycles) for 12 months were investigated. Moreover, a sustained loading factor was included in the test to reflect the behavior of the GFRP profiles in real structures. A normalization approach based on the controlled specimens was used to assess the effectiveness and relevance of the accelerated exposure. The results indicated that the maximum moisture absorption of both UP and VE GFRP profiles was immersed in deionized water, where the masses increased by 1.03 and 0.53%, respectively, leading to the maximum degradation of tensile strength (24.03%) of UP GFRP profile immersion in deionized water after 360 days of aging. However, the tensile modulus was more sensitive to high temperatures and has the maximum degradation (47.03%) after hygrothermal cycles. Moreover, VE GFRP profiles show superior humidity and temperature endurance. Furthermore, the sustained loading exacerbated the degradation of tensile properties slightly under the same conditions. Finally, by incorporating the cumulative damage caused by the sustained loading and a time-dependent factor into a residual strength model, a revised model was proposed to describe the tensile strength loss of pultruded UP GFRP profiles.
Reducing Changeover Time Between Surgeries Through Lean Thinking: An Action Research Project
Authors: Amati Mirjam , Valnegri Alan , Bressan Alessandro , La Regina Davide , Tassone Claudio , Lo Piccolo Antonio , Mongelli Francesco , Saporito Andrea
Published: April 2022

Background

Maximizing the utilization of the operating room suite by safely and efficiently changing over patients is an opportunity to deliver more value to patients and be more efficient in the operating suite. Lean Thinking is a concept that focuses on the waste inadvertently generated during organization and development of an activity, which should maximize customer value while minimizing waste. It has been widely applied to increase process efficiency and foster continuous improvement in healthcare and in the operating room environment. The objective of this paper is to provide insight on how healthcare professionals can be engaged in continuous improvement by embracing Lean Thinking and ultimately reducing changeover time between surgeries.

Methods

Using an action research approach, Lean methodology such as Gemba walks, Process Mapping, Root-Cause-Analysis, and the Single Minute Exchange of Dies (SMED) system was applied to understand the causes of variability and wastes concerning changeovers and improve processes in the context of gynecological- and general surgery. Data were collected and analyzed through observations and video recordings. Problem and issue have been raised to management team attention and included in the annual balanced scorecard of the hospital. This initiative has been also made relevant to the team working in the operating suite and related processes before and after the entry of the patient in the operating suite.

Results

Improved patient flow and inter-professional collaboration through standardized and safer work enabled effective parallel processing and allowed the hospital to reduce changeover time between operations by 25% on average, without changes in terms of infrastructure, technology or resources.

Conclusion

Lean thinking allowed the team to re-evaluate how the whole operating suite performs as a system, by starting from a sub-process as changeover. It is fundamental in order to improve further and obtain sustainable results over time, to act on a system level by defining a common goal between all stakeholders supported by a management and leading system such as visual/weekly management, optimizing planning, implementing standard-works to be followed by every associate and guaranteeing the role of the surgeon as process driver who pull performances.
Case Report: Use of Amniotic Membrane for Tectonic Repair of Peripheral Ulcerative Keratitis With Corneal Perforation
Authors: Eslami Maryam , Benito-Pascual Blanca , Goolam Saadiah , Trinh Tanya , Moloney Greg
Published: April 2022

Purpose

To provide a perspective and surgical video demonstration of peripheral corneal ulceration and perforation managed with multilayered amniotic membrane transplantation.

Case Reports

Case 1 describes a 48-year-old female with progressive redness and pain, and an inferonasal corneal thinning and perforation in the left eye from peripheral ulcerative keratitis. She underwent conjunctival recession with amniotic membrane inlay and onlay (Sandwich technique) transplantation. The amniotic membrane integrated well, and her Snellen visual acuity improved from 6/21 preoperatively to 6/9 at 3 months post op. Case 2 describes a 78-year-old male with redness and pain with temporal corneal thinning bilaterally and perforation in the right eye from peripheral ulcerative keratitis. Both eyes underwent similar surgical intervention with smooth integration of the amniotic membrane in the cornea and improvement in the visual acuity. Both patients were also started on systemic immunosuppression in collaboration with the rheumatology team.

Conclusion

We report successful use of multilayered amniotic membrane transplantation for the treatment of corneal ulceration and perforation. The authors believe the simplicity of the surgical technique, easier access to amniotic membrane tissue, and lower induced post-operative astigmatism all provide advantages over alternative treatment modalities.
Metabolic Basis of Cognitive Improvement Associated With Active B Vitamin Supplementation in Cognitively Impaired Elderly Subjects – A Metabolomics Study
Authors: Zhou Haiming , Wu Yuanyuan , Jiang Binhua , Li Bowen , Li Martin , Tian He , Shui Guanghou , Lam Sin Man , Kwok Timothy
Published: April 2022

Intervention studies with active B vitamin supplementation in cognitively impaired individuals have yielded varying results in randomized controlled trials. In addition, a negative interaction of active B vitamin supplementation with aspirin usage on cognitive outcome was noted, but the molecular basis of the interaction has largely remained unknown. To investigate the metabolic basis of cognitive improvement brought about by active B vitamin supplementation, we conducted an extensive metabolomics analysis covering 302 identified metabolites on the baseline and 24-month serum samples from a cohort of 137 subjects randomly assigned to active supplementation or placebo. Pathway analysis uncovered enhanced gluconeogenesis and War-burg effects underlying cognitive improvement in non-aspirin users supplemented with active B vitamins. In addition, metabolomics revealed that aspirin usage may interact with B vitamin supplementation by altering gut microbial metabolism, particularly in terms of propionate production. Lastly, our omics data suggest that varying capacities to assimilate B vitamins at baseline, possibly mediated by differences in gut microbial composition, may underlie variations in inter-individual responses to active B vitamin supplementation.
A Novel Neutrophil-Based Biomarker to Monitor Disease Activity and Predict Response to Infliximab Therapy in Patients With Ulcerative Colitis
Authors: Zhou Zhou , Zhang Yinghui , Pan Yan , Yang Xue , Li Liangping , Gao Caiping , He Chong
Published: April 2022

Background

Ulcerative colitis (UC) is characterized by refractory and recurrent mucosal inflammation, leading to a substantial healthcare burden. Diagnostic biomarkers predicting disease activity and treatment response remain elusive. To evaluate the application value of a novel neutrophil-based index (the neutrophil-to-albumin ratio, NAR) as a novel diagnostic biomarker in patients with UC and a predictive marker for disease activity and response to infliximab (IFX) therapy.

Methods

Clinical characteristics and laboratory parameters of enrolled subjects (patients with UC and healthy controls) were retrieved from the electronic medical record database of our hospital. Serum cytokine and fecal calprotectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Mucosal expression levels of inflammatory agents were measured by quantitative RT-PCR (qRT-PCR).

Results

We found that NAR, which had not yet been explored in UC, was significantly increased in patients with UC (n = 146) compared to that in controls (n = 133) (1.95 ± 0.41 vs. 1.41 ± 0.23, p < 0.0001). NAR showed a positive association with the disease activity and inflammatory load in patients with UC. Pre-treatment NAR was significantly lower in IFX responders than that in non-responders (2.18 ± 0.29 vs. 2.44 ± 0.21, p = 0.0118), showing a significant ability to discriminate initial responders from primary non-responders to IFX induction therapy (AUC = 0.7866, p = 0.0076). Moreover, pre-treatment NAR predicted postinduction serum IFX trough level.

Conclusion

Our study provides evidences to utilize NAR in the diagnosis, activity monitoring, and IFX response prediction in patients with UC.
Association Between Different DVT Prevention Methods and Outcomes of Septic Shock Caused by Intestinal Perforation in China: A Cross-Sectional Study
Authors: Wang Lu , Ma Xudong , He Huaiwu , Su Longxiang , Guo Yanhong , Shan Guangliang , Wang Ye , Zhou Xiang , Liu Dawei , Long Yun
Published: April 2022

Introduction

Septic shock, largely caused by intestinal perforation, is the most common critical illness in intensive care unit (ICU). As an important quality control strategy in ICU, deep vein thrombosis (DVT) prevention is routinely used in the treatment of septic shock. Nevertheless, the effects of DVT prevention on septic shock are not fully revealed. This study was thus designed to investigate the effects of DVT prevention on septic shock caused by intestinal perforation in China.

Methods

A total of 463 hospitals were enrolled in a survey, led by the China National Critical Care Quality Control Center (China NCCQC) from January 1, 2018 to December 31, 2018. The association between DVT prevention, including pharmacological prophylaxis and mechanical prophylaxis, and outcomes, such as prognosis, complications, hospital stays, and hospitalization costs, was determined in the present study.

Main Results

Notably, the increased rates of DVT prevention were not associated with the onset of complications in patients with septic shock caused by intestinal perforation (p > 0.05). In addition, even though increased DVT prevention did not affect hospital stays, it significantly decreased the discharge rates without doctor's order in patients with septic shock caused by intestinal perforation (p < 0.05). Nevertheless, it should be noted that the rates of pharmacological prophylaxis but not mechanical prophylaxis were significantly associated with the costs of septic shock caused by intestinal perforation (p < 0.05). Although increased total rates of DVT prevention and the rates of mechanical prophylaxis did not reduce the mortality in patients with septic shock caused by intestinal perforation, the higher frequent intervention using pharmacological prophylaxis indicated the lower mortality of these patients (p < 0.05).

Conclusions

DVT prevention by any means is a safe therapeutic strategy for treating septic shock caused by intestinal perforation, and pharmacological prophylaxis reduced the mortality of patients with septic shock caused by intestinal perforation.