bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Derived Neutrophil-To-Lymphocyte Ratio With Prognosis of Coronary Heart Disease After PCI
Authors: Liu Gang-Qiong , Zhang Wen-Jing , Shangguan Jia-Hong , Zhu Xiao-Dan , Wang Wei , Guo Qian-Qian , Zhang Jian-Chao , Wang Kai , Liu Zhi-Yu , Song Feng-Hua , Fan Lei , Zheng Ying-Ying , Zhang Jin-Ying
Published: September 2021

Aims: The present study aimed to investigate the prognostic role of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with coronary heart disease (CHD) after PCI.

Methods: A total of 3,561 post-PCI patients with CHD were retrospectively enrolled in the CORFCHD-ZZ study from January 2013 to December 2017. The patients (3,462) were divided into three groups according to dNLR tertiles: the first tertile (dNLR < 1.36; n = 1,139), second tertile (1.36 ≥ dNLR < 1.96; n = 1,166), and third tertile(dNLR ≥ 1.96; n = 1,157). The mean follow-up time was 37.59 ± 22.24 months. The primary endpoint was defined as mortality (including all-cause death and cardiac death), and the secondary endpoint was major adverse cardiovascular events (MACEs) and major adverse cardiovascular and cerebrovascular events (MACCEs).

Results: There were 2,644 patients with acute coronary syndrome (ACS) and 838 patients with chronic coronary syndrome (CCS) in the present study. In the total population, the all-cause mortality (ACM) and cardiac mortality (CM) incidence was significantly higher in the third tertile than in the first tertile [hazard risk (HR) = 1.8 (95% CI: 1.2–2.8), p = 0.006 and HR = 2.1 (95% CI: 1.23–3.8), p = 0.009, respectively]. Multivariate Cox regression analyses suggested that compared with the patients in the first tertile than those in the third tertile, the risk of ACM was increased 1.763 times (HR = 1.763, 95% CI: 1.133–2.743, p = 0.012), and the risk of CM was increased 1.763 times (HR = 1.961, 95% CI: 1.083–3.550, p = 0.026) in the higher dNLR group during the long-term follow-up. In both ACS patients and CCS patients, there were significant differences among the three groups in the incidence of ACM in univariate analysis. We also found that the incidence of CM was significantly different among the three groups in CCS patients in both univariate analysis (HR = 3.541, 95% CI: 1.154–10.863, p = 0.027) and multivariate analysis (HR = 3.136, 95% CI: 1.015–9.690, p = 0.047).

Conclusion: The present study suggested that dNLR is an independent and novel predictor of mortality in CHD patients who underwent PCI.
Activity Tracking Using Ear-Level Accelerometers
Authors: Skoglund Martin A. , Balzi Giovanni , Jensen Emil Lindegaard , Bhuiyan Tanveer A. , Rotger-Griful Sergi
Published: September 2021

Introduction: By means of adding more sensor technology, modern hearing aids (HAs) strive to become better, more personalized, and self-adaptive devices that can handle environmental changes and cope with the day-to-day fitness of the users. The latest HA technology available in the market already combines sound analysis with motion activity classification based on accelerometers to adjust settings. While there is a lot of research in activity tracking using accelerometers in sports applications and consumer electronics, there is not yet much in hearing research.

Objective: This study investigates the feasibility of activity tracking with ear-level accelerometers and how it compares to waist-mounted accelerometers, which is a more common measurement location.

Method: The activity classification methods in this study are based on supervised learning. The experimental set up consisted of 21 subjects, equipped with two XSens MTw Awinda at ear-level and one at waist-level, performing nine different activities.

Results: The highest accuracy on our experimental data as obtained with the combination of Bagging and Classification tree techniques. The total accuracy over all activities and users was 84% (ear-level), 90% (waist-level), and 91% (ear-level + waist-level). Most prominently, the classes, namely, standing, jogging, laying (on one side), laying (face-down), and walking all have an accuracy of above 90%. Furthermore, estimated ear-level step-detection accuracy was 95% in walking and 90% in jogging.

Conclusion: It is demonstrated that several activities can be classified, using ear-level accelerometers, with an accuracy that is on par with waist-level. It is indicated that step-detection accuracy is comparable to a high-performance wrist device. These findings are encouraging for the development of activity applications in hearing healthcare.
Organic Molecular Paleohypsometry: A New Approach to Quantifying Paleotopography and Paleorelief
Authors: Hren Michael T. , Ouimet William
Published: September 2021

Stable isotope paleoaltimetry is one of the most commonly used approaches for quantifying the paleoelevation history of an orogen yet this methodology is often limited to arid to semi-arid climates, mountain systems with a clear orographic rainshadow and terrestrial basins. We present a new approach to reconstructing past topography and relief that uses the catchment-integrated signature of organic molecular biomarkers to quantify the hypsometry of fluvially-exported biomass. Because terrestrially-produced biomolecules are synthesized over the full range of global climate conditions and can be preserved in both terrestrial and marine sediments, the geochemistry of fluvially-transported sedimentary biomarkers can provide a means of interrogating the evolution of topography for a range of environments and depositional settings, including those not well suited for a traditional isotope paleoaltimetry approach. We show an example from Taiwan, a rapidly eroding tropical mountain system that is characterized by high rates of biomass production and short organic residence time and discuss key factors that can influence molecular isotope signal production, transport and integration. Data show that in high relief catchments of Taiwan, river sediments can record integration of biomass produced throughout the catchment. Sedimentary biomarker δ2HnC29 in low elevation river deposition sites is generally offset from the δ2HnC29 value observed in local soils and consistent with an isotope composition of organics produced at the catchment mean elevation. We test the effect of distinct molecular production and erosion functions on the expected δ2HnC29 in river sediments and show that elevation-dependent differences in the production and erosion of biomarkers/sediment may yield only modest differences in the catchment-integrated isotopic signal. Relating fluvial biomarker isotope records to quantitative estimates of organic source elevations in other global orogens will likely pose numerous challenges, with a number of variables that influence molecular production and integration in a river system. We provide a discussion of important parameters that influence molecular biomarker isotope signatures in a mountain system and a framework for employing a molecular paleohypsometry approach to quantifying the evolution of other orogenic systems.
Soluble Klotho Is Decreased in Children With Type 1 Diabetes and Correlated With Metabolic Control
Authors: Zubkiewicz-Kucharska Agnieszka , Wikiera Beata , Noczyńska Anna
Published: September 2021

Klotho concentration may be considered as a prognostic factor in the development of chronic complications of diabetes. Moreover, decrease in sKlotho concentration may contribute to beta cell apoptosis and type 1 diabetes development. The aim of this study was to evaluate if sKlotho protein concentration in children with type 1 diabetes (T1D) and its correlation with classical risk factors of chronic complications of diabetes: dysglycemia and endothelial dysfunction.

Material and methods

In a cross-section single center study the levels of soluble Klotho protein in 80 T1D (37 boys) and 34 healthy children (controls, 15 boys). Micro- and macroangiopathy were excluded and renal function was normal in all participants. Serum sKlotho, sICAM-1, sVCAM-1 and E-selectin levels were measured.

Results

The concentration of sKlotho was lower in T1D than in the controls (2041.9 ± 1017.6 pg/mL vs. 2790.3 ± 1423.9 pg/mL, p=0.0113). sICAM-1, sVCAM-1 and E-selectin concentrations were comparable in patients and controls. In T1D, sKlotho was not correlated with the duration of diabetes. Klotho and E-selectin were correlated with HbA1c (r=-0.31, P=0.0066 and r=0.25, P=0.0351, respectively), but not with AVBG and blood glucose SD. Correlations of sKlotho with total cholesterol (r=0.31, P=0.0129), HDL-cholesterol (r=0.43, P=0.0011) and LDL-cholesterol (r=0.28, P=0.0412), but not with triglycerides, were found. Likewise, Klotho was not correlated with sICAM-1, sVCAM-1, and E-selectin concentrations.

Conclusions

This study reports the significantly lower level of s-Klotho in children with type 1 diabetes, correlated with HbA1c and HDL cholesterol, but not with the adhesion molecules concentrations nor the duration of the disease. Negative correlation between the levels of HbA1c and soluble Klotho may suggest its possible involvement in the development of chronic diabetes complications.
Multi-Time Scale Economic Optimization Dispatch of the Park Integrated Energy System
Authors: Li Peng , Zhang Fan , Ma Xiyuan , Yao Senjing , Zhong Zhuolin , Yang Ping , Zhao Zhuoli , Lai Chun Sing , Lai Loi Lei
Published: September 2021

The park integrated energy system (PIES) plays an important role in realizing sustainable energy development and carbon neutral. Furthermore, its optimization dispatch can improve the energy utilization efficiency and reduce energy systems operation cost. However, the randomness and volatility of renewable energy and the instability of load all bring challenges to its optimal operation. An optimal dispatch framework of PIES is proposed, which constructs the operation models under three different time scales, including day-ahead, intra-day and real-time. Demand response is also divided into three levels considering its response characteristics and cost composition under different time scales. The example analysis shows that the multi-time scale optimization dispatch model can not only meet the supply and demand balance of PIES, diminish the fluctuation of renewable energy and flatten load curves, but also reduce the operation cost and improve the reliability of energy systems.
Characterization of Modification Patterns, Biological Function, Clinical Implication, and Immune Microenvironment Association of m6A Regulators in Pancreatic Cancer
Authors: Fang Kun , Qu Hairong , Wang Jiapei , Tang Desheng , Yan Changsheng , Ma Jiamin , Gao Lei
Published: September 2021

Objective: N6-methyladenosine (m6A) modification may modulate various biological processes. Nonetheless, clinical implications of m6A modification in pancreatic cancer are undefined. Herein, this study comprehensively characterized the m6A modification patterns in pancreatic cancer based on m6A regulators.

Methods: Genetic mutation and expression pattern of 21 m6A regulators and their correlations were assessed in pancreatic cancer from TCGA dataset. m6A modification patterns were clustered using unsupervised clustering analysis in TCGA and ICGC datasets. Differences in survival, biological functions and immune cell infiltrations were assessed between modification patterns. A m6A scoring system was developed by principal component analysis. Genetic mutations and TIDE scores were compared between high and low m6A score groups.

Results: ZC3H13 (11%), RBM15B (9%), YTHDF1 (8%), and YTHDC1 (6%) frequently occurred mutations among m6A regulators. Also, most of regulators were distinctly dysregulated in pancreatic cancer. There were tight crosslinks between regulators. Two m6A modification patterns were constructed, with distinct prognoses, immune cell infiltration and biological functions. Furthermore, we quantified m6A score in each sample. High m6A scores indicated undesirable clinical outcomes. There were more frequent mutations in high m6A score samples. Lower TIDE score was found in high m6A score group, with AUC = 0.61, indicating that m6A scores might be used for predicting the response to immunotherapy.

Conclusion: Collectively, these data demonstrated that m6A modification participates pancreatic cancer progress and ornaments immune microenvironment, providing an insight into pancreatic cancer pathogenesis and facilitating precision medicine development.
Barrett’s Epithelium to Esophageal Adenocarcinoma: Is There a “Point of No Return”?
Authors: Panda Anshuman , Shin Mi ryung , Cheng Christina , Bajpai Manisha
Published: September 2021

Background: Esophageal adenocarcinoma (EA) arises from Barrett’s epithelium (BE), and chronic gastroesophageal reflux disease is considered the strongest risk factor for disease progression. All BE patients undergo acid suppressive therapy, surveillance, and BE removal by surgery or endoscopic ablation, yet the incidence of EAC continues to increase. Despite the known side effects and mortality, the one-size-fits-all approach is the standard clinical management as there are no reliable methods for risk stratification.

Methods: Paired-end Illumina NextSeq500 RNA sequencing was performed on total RNA extracted from 20-week intervals (0, 20, 40, and 60 W) of an in vitro BE carcinogenesis (BEC) model to construct time series global gene expression patterns (GEPs). The cells from two strategic time points (20 and 40 W) based on the GEPs were grown for another 20 weeks, with and without further acid and bile salt (ABS) stimulation, and the recurrent neoplastic cell phenotypes were evaluated.

Results: Hierarchical clustering of 866 genes with ≥ twofold change in transcript levels across the four time points revealed maximum variation between the BEC20W and BEC40W cells. Enrichment analysis confirmed that the genes altered ≥ twofold during this window period associated with carcinogenesis and malignancy. Intriguingly, the BEC20W cells required further ABS exposure to gain neoplastic changes, but the BEC40W cells progressed to malignant transformation after 20 weeks even in the absence of additional ABS.

Discussion: The transcriptomic gene expression patterns in the BEC model demonstrate evidence of a clear threshold in the progression of BE to malignancy. Catastrophic transcriptomic changes during a window period culminate in the commitment of the BE cells to a “point of no return,” and removal of ABS is not effective in preventing their malignant transformation. Discerning this “point of no return” during BE surveillance by tracking the GEPs has the potential to evaluate risk of BE progression and enable personalized clinical management.
Impact of Amplification Efficiency Approaches on Telomere Length Measurement via Quantitative-Polymerase Chain Reaction
Authors: Hastings Waylon J. , Eisenberg Dan T. A. , Shalev Idan
Published: September 2021

Background: Precise determination of amplification efficiency is critical for reliable conversion of within-sample changes in fluorescence occurring on a logarithmic scale to between-sample differences in DNA content occurring on a linear scale. This endeavor is especially challenging for the telomere length (TL) quantitative-PCR (qPCR) assay, where amplification efficiency can vary between reactions targeting telomeric repeats (T) and those targeting a single-copy gene (S) to calculate TL as the T/S ratio.

Methods: We compared seven different approaches toward estimating amplification efficiency, including the standard-curve method utilized by the qPCR instrument software, and alternative approaches which estimate efficiency on a reaction-by-reaction basis using the stand-alone program LinRegPCR. After calculating T/S ratios using efficiency estimates from each approach (N = 363), we tested their relative performance on metrics of assay precision and correlates of external validity including chronological age (age range = 1–72 years), across tissues within-person (leukocyte-buccal), and between parents and offspring.

Results: Estimated amplification efficiency for telomere reactions was significantly lower than estimates for single-copy gene reactions. Efficiency estimates for both reaction sets were significantly higher when estimated with the standard-curve method utilized by the qPCR instrument relative to estimates reconstructed during the log-linear phase with LinRegPCR. While estimates of single-copy gene efficiency reconstructed using LinRegPCR measured within 90% of perfect exponential doubling (E = 1.92), estimates generated using the standard-curve method were inflated beyond 100% (E = 2.10–2.12), indicating poor fidelity. Despite differences in raw value, TL measurements calculated with LinRegPCR efficiency estimates exhibited similar relationships with external validity correlates to measurements generated using the qPCR instrument software.

Conclusion: Since methods to estimate amplification efficiency can vary across qPCR instruments, we suggest that future analyses empirically consider external methods of efficiency calculations such as LinRegPCR, and that already generated data be re-analyzed to glean possible improvements.
HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity
Authors: Zhou Jinghang , Liu Liyuan , Lopdell Thomas J. , Garrick Dorian J. , Shi Yuangang
Published: September 2021

Detection of CNVs (copy number variants) and ROH (runs of homozygosity) from SNP (single nucleotide polymorphism) genotyping data is often required in genomic studies. The post-analysis of CNV and ROH generally involves many steps, potentially across multiple computing platforms, which requires the researchers to be familiar with many different tools. In order to get around this problem and improve research efficiency, we present an R package that integrates the summarization, annotation, map conversion, comparison and visualization functions involved in studies of CNV and ROH. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving, and user-friendly for researchers in humans and most diploid livestock species.
A Pan-Cancer Analysis of Cystatin E/M Reveals Its Dual Functional Effects and Positive Regulation of Epithelial Cell in Human Tumors
Authors: Xu Dahua , Ding Shun , Cao Meng , Yu Xiaorong , Wang Hong , Qiu Dongqin , Xu Zhengyang , Bi Xiaoman , Mu Zhonglin , Li Kongning
Published: September 2021

Cystatin E/M (CST6), a representative cysteine protease inhibitor, plays both tumor-promoting and tumor-suppressing functions and is pursued as an epigenetically therapeutic target in special cancer types. However, a comprehensive and systematic analysis for CST6 in pan-cancer level is still lacking. In the present study, we explored the expression pattern of CST6 in multiple cancer types across ∼10,000 samples from TCGA (The Cancer Genome Atlas) and ∼8,000 samples from MMDs (Merged Microarray-acquired Datasets). We found that the dynamic expression alteration of CST6 was consistent with dual function in different types of cancer. In addition, we observed that the expression of CST6 was globally regulated by the DNA methylation in its promoter region. CST6 expression was positively correlated with the epithelial cell infiltration involved in epithelial-to-mesenchymal transition (EMT) and proliferation. The relationship between CST6 and tumor microenvironment was also explored. In particular, we found that CST6 serves a protective function in the process of melanoma metastasis. Finally, the clinical association analysis further revealed the dual function of CST6 in cancer, and a combination of the epithelial cell infiltration and CST6 expression could predict the prognosis for SKCM patients. In summary, this first CST6 pan-cancer study improves the understanding of the dual functional effects on CST6 in different types of human cancer.
Extracellular Matrix-Induced GM-CSF and Hypoxia Promote Immune Control of Mycobacterium tuberculosis in Human In Vitro Granulomas
Authors: Arbués Ainhoa , Schmidiger Sarah , Kammüller Michael , Portevin Damien
Published: September 2021

Several in vitro cellular models have been developed with the aim to reproduce and dissect human granulomatous responses, the hallmark of tuberculosis (TB) immunopathogenesis. In that context, we compared two- (2D) versus three-dimensional (3D) granuloma models resulting from infection of human peripheral blood mononuclear cells with M. tuberculosis (Mtb) in the absence or presence of a collagen-based extracellular matrix (ECM). Granuloma formation was found to be significantly enhanced in the 2D model. This feature was associated with an earlier chemokine production and lymphocyte activation, but also a significantly increased bacterial burden. Remarkably, the reduction in Mtb burden in the 3D model correlated with an increase in GM-CSF production. GM-CSF, which is known to promote macrophage survival, was found to be inherently induced by the ECM. We observed that only 3D in vitro granulomas led to the accumulation of lipid inclusions within Mtb. Our data suggest that a hypoxic environment within the ECM could be responsible for this dormant-like Mtb phenotype. Furthermore, exposure to a TNF-α antagonist reverted Mtb dormancy, thereby mimicking the reactivation of TB observed in rheumatic patients receiving this therapy. To conclude, we showed that only in vitro granulomas generated in the presence of an ECM could recapitulate some clinically relevant features of granulomatous responses in TB. As such, this model constitutes a highly valuable tool to study the interplay between immunity and Mtb stress responses as well as to evaluate novel treatment strategies.
A Systematic Review of the Tumor-Infiltrating CD8+ T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology
Authors: Shadbad Mahdi Abdoli , Asadzadeh Zahra , Hosseinkhani Negar , Derakhshani Afshin , Alizadeh Nazila , Brunetti Oronzo , Silvestris Nicola , Baradaran Behzad
Published: September 2021

Based on preclinical findings, programmed death-ligand 1 (PD-L1) can substantially attenuate CD8+ T-cell-mediated anti-tumoral immune responses. However, clinical studies have reported controversial results regarding the significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis on the clinical picture and the response rate of patients with high-grade glial tumors to anti-cancer therapies. Herein, we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements to clarify the clinical significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis and elucidate the impact of this axis on the response rate of affected patients to anti-cancer therapies. Indeed, a better understanding of the impact of this axis on the response rate of affected patients to anti-cancer therapies can provide valuable insights to address the futile response rate of immune checkpoint inhibitors in patients with high-grade glial tumors. For this purpose, we systematically searched Scopus, Web of Science, Embase, and PubMed to obtain peer-reviewed studies published before 1 January 2021. We have observed that PD-L1 overexpression can be associated with the inferior prognosis of glioblastoma patients who have not been exposed to chemo-radiotherapy. Besides, exposure to anti-cancer therapies, e.g., chemo-radiotherapy, can up-regulate inhibitory immune checkpoint molecules in tumor-infiltrating CD8+ T-cells. Therefore, unlike unexposed patients, increased tumor-infiltrating CD8+ T-cells in anti-cancer therapy-exposed tumoral tissues can be associated with the inferior prognosis of affected patients. Because various inhibitory immune checkpoints can regulate anti-tumoral immune responses, the single-cell sequencing of the cells residing in the tumor microenvironment can provide valuable insights into the expression patterns of inhibitory immune checkpoints in the tumor micromovement. Thus, administrating immune checkpoint inhibitors based on the data from the single-cell sequencing of these cells can increase patients’ response rates, decrease the risk of immune-related adverse events development, prevent immune-resistance development, and reduce the risk of tumor recurrence.
Recognition of Tumor-Associated Antigens and Immune Subtypes in Glioma for mRNA Vaccine Development
Authors: Ma Shuai , Ba Yixu , Ji Hang , Wang Fang , Du Jianyang , Hu Shaoshan
Published: September 2021

Background

Although mRNA vaccines have been efficient for combating a variety of tumors, their effectiveness against glioma remains unclear. There is growing evidence that immunophenotyping can reflect the comprehensive immune status and microenvironment of the tumor, which correlates closely with treatment response and vaccination potency. The purpose of this research was to screen for effective antigens in glioma that could be used for developing mRNA vaccines and to further differentiate the immune subtypes of glioma to create an selection criteria for suitable patients for vaccination.

Methods

Gene expression profiles and clinical data of 698 glioma samples were extracted from The Cancer Genome Atlas, and RNA_seq data of 1018 glioma samples was gathered from Chinese Glioma Genome Atlas. Gene Expression Profiling Interactive Analysis was used to determine differential expression genes and prognostic markers, cBioPortal software was used to verify gene alterations, and Tumor Immune Estimation Resource was used to investigate the relationships among genes and immune infiltrating cells. Consistency clustering was applied for consistent matrix construction and data aggregation, Gene oncology enrichment was performed for functional annotation, and a graph learning-based dimensionality reduction method was applied to describe the subtypes of immunity.

Results

Four overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in glioma, including TP53, IDH1, C3, and TCF12. Besides, four immune subtypes of glioma (IS1-IS4) and 10 immune gene modules were identified consistently in the TCGA data. The immune subtypes had diverse molecular, cellular, and clinical features. IS1 and IS4 displayed an immune-activating phenotype and were associated with worse survival than the other two subtypes, while IS2 and IS3 had lower levels of tumor immune infiltration. Immunogenic cell death regulators and immune checkpoints were also diversely expressed in the four immune subtypes.

Conclusion

TP53, IDH1, C3, and TCF12 are effective antigens for the development of anti-glioma mRNA vaccines. We found four stable and repeatable immune subtypes of human glioma, the classification of the immune subtypes of glioma may play a crucial role in the predicting mRNA vaccine outcome.
Successful Treatment of Advanced Intrahepatic Cholangiocarcinoma With a High Tumor Mutational Burden and PD-L1 Expression by PD-1 Blockade Combined With Tyrosine Kinase Inhibitors: A Case Report
Authors: Zhang Ze , Zhang Wenwen , Wang Hongguang , Hu Bingyang , Wang Zhanbo , Lu Shichun
Published: September 2021

Advanced intrahepatic cholangiocarcinoma (iCCA) is not suitable for surgical treatment. Guided by the concept of precision medicine, preoperative systematic treatment may reshape the clinical outcomes of advanced intrahepatic cholangiocarcinoma patients. We describe the case of a 38-year-old female who has been diagnosed with stage IV intrahepatic cholangiocarcinoma with a high tumor mutational burden and positively programmed death-ligand 1 (PD-L1) expression. The patient was treated with programmed cell death 1 (PD-1) inhibitors combined with tyrosine kinase inhibitors (TKIs). After 7 cycles of combination therapy, she underwent radical resection and no tumor cells were found in the postoperative histopathological examination. In addition, the patient’s survival time had reached 25 months, as of August 2021. To date, this is the first case of successful radical resection after combined immunotherapy with TKIs for advanced PD-L1-positive intrahepatic cholangiocarcinoma with a high tumor mutational burden (TMB). The case provides a new approach to the treatment of advanced intrahepatic cholangiocarcinoma.
A Machine Learning Model to Predict the Triple Negative Breast Cancer Immune Subtype
Authors: Chen Zihao , Wang Maoli , De Wilde Rudy Leon , Feng Ruifa , Su Mingqiang , Torres-de la Roche Luz Angela , Shi Wenjie
Published: September 2021

Background

Immune checkpoint blockade (ICB) has been approved for the treatment of triple-negative breast cancer (TNBC), since it significantly improved the progression-free survival (PFS). However, only about 10% of TNBC patients could achieve the complete response (CR) to ICB because of the low response rate and potential adverse reactions to ICB.

Methods

Open datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were downloaded to perform an unsupervised clustering analysis to identify the immune subtype according to the expression profiles. The prognosis, enriched pathways, and the ICB indicators were compared between immune subtypes. Afterward, samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were used to validate the correlation of immune subtype with prognosis. Data from patients who received ICB were selected to validate the correlation of the immune subtype with ICB response. Machine learning models were used to build a visual web server to predict the immune subtype of TNBC patients requiring ICB.

Results

A total of eight open datasets including 931 TNBC samples were used for the unsupervised clustering. Two novel immune subtypes (referred to as S1 and S2) were identified among TNBC patients. Compared with S2, S1 was associated with higher immune scores, higher levels of immune cells, and a better prognosis for immunotherapy. In the validation dataset, subtype 1 samples had a better prognosis than sub type 2 samples, no matter in overall survival (OS) (p = 0.00036) or relapse-free survival (RFS) (p = 0.0022). Bioinformatics analysis identified 11 hub genes (LCK, IL2RG, CD3G, STAT1, CD247, IL2RB, CD3D, IRF1, OAS2, IRF4, and IFNG) related to the immune subtype. A robust machine learning model based on random forest algorithm was established by 11 hub genes, and it performed reasonably well with area Under the Curve of the receiver operating characteristic (AUC) values = 0.76. An open and free web server based on the random forest model, named as triple-negative breast cancer immune subtype (TNBCIS), was developed and is available from https://immunotypes.shinyapps.io/TNBCIS/.

Conclusion

TNBC open datasets allowed us to stratify samples into distinct immunotherapy response subgroups according to gene expression profiles. Based on two novel subtypes, candidates for ICB with a higher response rate and better prognosis could be selected by using the free visual online web server that we designed.
Conceptual Advances in Control of Inflammation by the RNA-Binding Protein Tristetraprolin
Authors: Kovarik Pavel , Bestehorn Annika , Fesselet Jeanne
Published: September 2021

Regulated changes in mRNA stability are critical drivers of gene expression adaptations to immunological cues. mRNA stability is controlled mainly by RNA-binding proteins (RBPs) which can directly cleave mRNA but more often act as adaptors for the recruitment of the RNA-degradation machinery. One of the most prominent RBPs with regulatory roles in the immune system is tristetraprolin (TTP). TTP targets mainly inflammation-associated mRNAs for degradation and is indispensable for the resolution of inflammation as well as the maintenance of immune homeostasis. Recent advances in the transcriptome-wide knowledge of mRNA expression and decay rates together with TTP binding sites in the target mRNAs revealed important limitations in our understanding of molecular mechanisms of TTP action. Such orthogonal analyses lead to the discovery that TTP binding destabilizes some bound mRNAs but not others in the same cell. Moreover, comparisons of various immune cells indicated that an mRNA can be destabilized by TTP in one cell type while it remains stable in a different cell linage despite the presence of TTP. The action of TTP extends from mRNA destabilization to inhibition of translation in a subset of targets. This article will discuss these unexpected context-dependent functions and their implications for the regulation of immune responses. Attention will be also payed to new insights into the role of TTP in physiology and tissue homeostasis.
Detailed Patterns of Methane Distribution in the German Bight
Authors: Bussmann Ingeborg , Brix Holger , Flöser Götz , Ködel Uta , Fischer Philipp
Published: September 2021

Although methane is a widely studied greenhouse gas, uncertainties remain with respect to the factors controlling its distribution and diffusive flux into the atmosphere, especially in highly dynamic coastal waters. In the southern North Sea, the Elbe and Weser rivers are two major tributaries contributing to the overall methane budget of the southern German Bight. In June 2019, we continuously measured methane and basic hydrographic parameters at a high temporal and spatial resolution (one measurement per minute every 200–300 m) on a transect between Cuxhaven and Helgoland. These measurements revealed that the overall driver of the coastal methane distribution is the dilution of riverine methane-rich water with methane-poor marine water. For both the Elbe and Weser, we determined an input concentration of 40–50 nmol/L compared to only 5 nmol/L in the marine area. Accordingly, we observed a comparatively steady dilution pattern of methane concentration toward the marine realm. Moreover, small-scale anomalous patterns with unexpectedly higher dissolved methane concentrations were discovered at certain sites and times. These patterns were associated with the highly significant correlations of methane with oxygen or turbidity. However, these local anomalies were not consistent over time (days, months). The calculated diffusive methane flux from the water into the atmosphere revealed local values approximately 3.5 times higher than background values (median of 36 and 128 μmol m–2d–1). We evaluate that this occurred because of a combination of increasing wind speed and increasing methane concentration at those times and locations. Hence, our results demonstrate that improved temporal and spatial resolution of methane measurements can provide a more accurate estimation and, consequently, a more functional understanding of the temporal and spatial dynamics of the coastal methane flux.
Melatonin as a Multipotent Component of Fish Feed: Basic Information for Its Potential Application in Aquaculture
Authors: Acharyya Akash , Das Joydeep , Hasan Kazi Nurul
Published: September 2021

In vertebrates, melatonin (N-acetyl-5-methoxy-tryptamine, MEL) is synthesized from L-tryptophan (L-Trp), primarily in the pineal gland and additionally in several non-pineal tissues, including enterochromaffin cells of the gastrointestinal tract. The biosynthesis of MEL in the pinealocytes exhibits a daily rhythm with a nocturnal peak in synchronization with the dark phase of an environment. However, the temporal pattern of the gut melatoninergic system in fish is known to be synchronized with one or more non-photic external cue(s), of which most notable include the components of food and feeding time in a daily cycle. Experimental findings on the use of L-Trp (5-fold to −8-fold higher with respect to standard) as a fish food supplement suggest that it has a stimulatory influence on gut MEL synthesis that ultimately leads to elevated levels of plasma MEL. Several studies employing MEL as a fish feed additive report variable responses in relation to the physiological functions of the fish and its doses of application and modes of exposure. Oral administration of MEL (validated dose in general: 200 mg/kg fish food) causes an increase in gut MEL concentrations, food intake capacity, and micronutrient selection ability of fish, as well as enhanced activity of antioxidative enzymes and/or reduced levels of biological stress markers like plasma cortisol and lactate. The application of MEL with the doses of 50 and 250 mg/kg fish food to balanced diet results in precious maturation of gonads, high live sperm rate, and good quality seeds in catfish. A few studies on different fish groups administered with MEL through tank water reveal a significant increase in the fecundity rate, percentage of fertilization, and the number of hatched embryos. MEL injection through intraperitoneal or intramuscular routes also elicits variable responses in fish. Several studies suggest a major protective role of endogenous MEL against gastric ulcer induced by pathogenic bacterial infection. Taken together, MEL seems to be a multipotent physiological candidate involved in the regulation of a variety of body functions ranging from the synchronization of vital activities with environmental variables to the timing of reproduction in a changing system, from the acceleration of body growth to the determination of a pattern of development, and from the reduction of oxidative stress to the protection against microbial infections. Because aquaculture aims at substantially improving the quality and quantity of available aquatic resources employing convenient, consistent, and commercially exploitable measures, we find the reasons to suggest that the use of MEL or its precursor L-Trp as a fish food supplement may open up a new vista of aquaculture and, hence, present this review with an attempt to present the basic information on this area of interest to justify the hypothesis.
Negative and Near-Zero Thermal Expansion in A2M3O12 and Related Ceramic Families: A Review
Authors: Marinkovic Bojan A. , Pontón Patricia I. , Romao Carl P. , Moreira Thaís , White Mary Anne
Published: September 2021

This review presents the history of materials in the A2M3O12 and related ceramic families, including their unusual thermal expansion and the present understanding of its mechanism, and related factors such as hydroscopicity and the monoclinic to orthorhombic phase transition. Other properties, including thermomechanical, thermal and ionic conduction and optical properties, are presented in terms of current knowledge, challenges and opportunities for applications. One of the largest challenges is the production of monoliths, and various methods for consolidation and sintering are summarized. These ceramics have considerable promise when combined with other materials, and recent advances in such composites are presented. These matters are placed in the context of the potential applications of negative and near-zero thermal expansion ceramics, which still present challenges for future materials researchers.
Community Structure and Function of Epiphytic Bacteria Associated With Myriophyllum spicatum in Baiyangdian Lake, China
Authors: Sun Lei , Wang Jiashuo , Wu Yangyang , Gao Tianyu , Liu Cunqi
Published: September 2021

Epiphytic bacteria on the surfaces of submerged macrophytes play important roles in the growth of the host plant, nutrient cycling, and the conversion of pollutants in aquatic systems. A knowledge of the epiphytic bacterial community structure could help us to understand these roles. In this study, the abundance, diversity, and functions of the epiphytic bacterial community of Myriophyllum spicatum collected from Baiyangdian Lake in June, August, and October 2019 were studied using quantitative PCR (qPCR), high-throughput sequencing, and the prediction of functions. An analysis using qPCR showed that the epiphytic bacteria were the most abundant in October and the least abundant in August. High-throughput sequencing revealed that Proteobacteria, Gammaproteobacteria, and Aeromonas were the dominant phylum, class, and genus in all the samples. The common analyses of operational taxonomic units (OTUs), NMDS, and LDA showed that the epiphytic bacterial communities were clustered together based on the seasons. The results of a canonical correlation analysis (CCA) showed that the key water quality index that affected the changes of epiphytic bacterial community of M. spicatum was the total phosphorus (TP). The changes in abundance of Gammaproteobacteria negatively correlated with the TP. Predictive results from FAPROTAX showed that the predominant biogeochemical cycle functions of the epiphytic bacterial community were chemoheterotrophy, nitrate reduction, and fermentation. These results suggest that the epiphytic bacterial community of M. spicatum from Baiyangdian Lake varies substantially with the seasons and environmental conditions.
Effect of the Histone Methyltransferase Specific Probe BRD4770 on Metabolic Profiling of the Endophytic Fungus Diaporthe longicolla
Authors: Nishad Jay Hind , Singh Arti , Bharti Rajnish , Prajapati Priyanka , Sharma Vijay Kumar , Gupta Vijai Kumar , Kharwar Ravindra Nath
Published: September 2021

The endophytic fungus Diaporthe longicolla was isolated from the stem of Saraca asoca (Roxb.) Willd., commonly known as Ashok plant in India and Sri Lanka. Since no reports are available regarding epigenetic modulations by BRD4770 in microbial entities, D. longicolla was treated with different concentrations of BRD4770 for this purpose and evaluated for its antioxidant and antibacterial potential against five human pathogenic bacteria, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Shigella boydii, Klebsiella pneumoniae, and Escherichia coli. The crude extract obtained from cultures treated with 100 nM concentration of BRD4770 showed increased antioxidant activity and inhibition zone against S. aureus and MRSA, compared to the non-treated control. The composition of the non-treated and treated crude extract was analyzed, and induced compounds were identified with the help of Gas chromatography–mass spectrometry (GC-MS) and LC-ESI-MS/MS. LC-ESI-MS/MS analysis showed that berberine (antibacterial)-, caffeine-, and theobromine (antioxidant)-like compounds were induced in the BRD4770-treated crude extract. The presence of particular absorbance at a wavelength of 346.5 nm for berberine, 259.4 nm for caffeine, and 278.4 nm for theobromine in the reverse-phase high-performance liquid chromatography (HPLC) analysis of both BRD4770-treated crude metabolites and standard solution of the above compounds strongly supported the increased antibacterial and antioxidant activities that may be due to inducing the alterations in bioactivities of the BRD4770-treated culture.
Growth and Characteristics of Two Different Epichloë sinensis Strains Under Different Cultures
Authors: Luo Yang , Tian Pei
Published: September 2021

In the present study, two Epichloë sinensis endophyte strains isolated from different Festuca sinensis ecotypes were inoculated on potato dextrose agar (PDA) and potato dextrose broth (PDB) media with or without (control) exogenous additives. After 4weeks of growth, the growth (colony diameter, hyphal diameter, and mycelial biomass) and other characteristics (pH and antioxidant capacity of culture filtrate, mycelial ion contents, and hormone contents) were measured. The results showed that the culture conditions had significant effects (p<0.05) on the hyphal diameter, mycelial biomass, and hormone content of the two strains. The mycelial biomass of the two strains in PDB was significantly higher (p<0.05) than that on PDA. Except for strain 1 with indole-3-acetic acid (IAA) treatment and strain 84F with control and VB1 treatments, the hyphal diameter of the two strains in PDB under the other treatments was significantly higher (p<0.05) than that on PDA. In most cases, the IAA, cytokinins (CTK), abscisic acid (ABA), and gibberlic acid (GA) contents in the mycelia on PDA of the two strains were significantly higher (p<0.05) than those in PDB. The two E. sinensis strains exhibited significantly different performances (p<0.05) under the five treatments. The indices, including colony diameter, mycelial biomass, scavenging ability of superoxide anion radicals and hydroxyl radicals, pH of culture filtrate, ion contents, hyphal diameter, and IAA, CTK, GA, and ABA contents were significantly different (p<0.05) between the two strains, although the performance was inconsistent. Exogenous additives had significant effects (p<0.05) on the performance of the two E. sinensis strains. Indole-3-acetic acid and VB1 treatments significantly promoted (p<0.05) the growth of the two strains on both PDA and PDB. Indole-3-acetic acid treatment also significantly increased the hyphal diameters of the two strains in PDB (p<0.05). Indole-3-acetic acid and VB1 treatments significantly reduced (p<0.05) the antioxidant ability of these two strains in PDB. NaCl and ZnCl2 treatments had significant inhibitory effects (p<0.05) on fungal growth and promotion effects on the antioxidant ability of the two strains. The treatments also had significant effects (p<0.05) on hyphal diameters and ion and hormone contents, although the effects varied with different indices.
Bacterial Composition Associated With Giant Colonies of the Harmful Algal Species Phaeocystis globosa
Authors: Zhu Zhu , Meng Rui , Smith Jr. Walker O. , Doan-Nhu Hai , Nguyen-Ngoc Lam , Jiang Xinjun
Published: September 2021

The cosmopolitan algae Phaeocystis globosa forms harmful algal blooms frequently in a number of tropical and subtropical coastal regions in the past two decades. During the bloom, the giant colony, which is formed by P. globosa, is the dominant morphotype. However, the microenvironment and the microbial composition in the intracolonial fluid are poorly understood. Here, we used high-throughput 16S rRNA amplicon sequencing to examine the bacterial composition and predicted functions in intracolonial fluid. Compared with the bacterial consortia in ambient seawater, intracolonial fluids possessed the lower levels of microbial richness and diversity, implying selectivity of bacteria by the unique intracolonial microenvironment enclosed within the P. globosa polysaccharide envelope. The bacterial consortia in intracolonial fluid were dominated by Balneola (48.6% of total abundance) and Labrezia (28.5%). The bacteria and microbial function enriched in intracolonial fluid were involved in aromatic benzenoid compounds degradation, DMSP and DMS production and consumption, and antibacterial compounds synthesis. We suggest that the P. globosa colonial envelope allows for the formation of a specific microenvironment; thus, the unique microbial consortia inhabiting intracolonial fluid has close interaction with P. globosa cells, which may benefit colony development.