bluuebunny/crossref_metadata_2025 huggingface dataset:
B Cell Signatures Distinguish Cutaneous Lupus Erythematosus Subtypes and the Presence of Systemic Disease Activity
Authors: Abernathy-Close Lisa , Lazar Stephanie , Stannard Jasmine , Tsoi Lam C. , Eddy Sean , Rizvi Syed M. , Yee Christine M. , Myers Emily M. , Namas Rajaie , Lowe Lori , Reed Tamra J. , Wen Fei , Gudjonsson Johann E. , Kahlenberg J. Michelle , Berthier Celine C.
Published: November 2021

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease characterized by a diverse cadre of clinical presentations. CLE commonly occurs in patients with systemic lupus erythematosus (SLE), and CLE can also develop in the absence of systemic disease. Although CLE is a complex and heterogeneous disease, several studies have identified common signaling pathways, including those of type I interferons (IFNs), that play a key role in driving cutaneous inflammation across all CLE subsets. However, discriminating factors that drive different phenotypes of skin lesions remain to be determined. Thus, we sought to understand the skin-associated cellular and transcriptional differences in CLE subsets and how the different types of cutaneous inflammation relate to the presence of systemic lupus disease. In this study, we utilized two distinct cohorts comprising a total of 150 CLE lesional biopsies to compare discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE) in patients with and without associated SLE. Using an unbiased approach, we demonstrated a CLE subtype-dependent gradient of B cell enrichment in the skin, with DLE lesions harboring a more dominant skin B cell transcriptional signature and enrichment of B cells on immunostaining compared to ACLE and SCLE. Additionally, we observed a significant increase in B cell signatures in the lesional skin from patients with isolated CLE compared with similar lesions from patients with systemic lupus. This trend was driven primarily by differences in the DLE subgroup. Our work thus shows that skin-associated B cell responses distinguish CLE subtypes in patients with and without associated SLE, suggesting that B cell function in skin may be an important link between cutaneous lupus and systemic disease activity.
Immunomodulation in the Treatment of Periodontitis: Progress and Perspectives
Authors: Yang Bo , Pang Xuefei , Li Zhipeng , Chen Zhuofan , Wang Yan
Published: November 2021

Periodontitis is one of the most common dental diseases. Compared with healthy periodontal tissues, the immune microenvironment plays the key role in periodontitis by allowing the invasion of pathogens. It is possible that modulating the immune microenvironment can supplement traditional treatments and may even promote periodontal regeneration by using stem cells, bacteria, etc. New anti-inflammatory therapies can enhance the generation of a viable local immune microenvironment and promote cell homing and tissue formation, thereby achieving higher levels of immune regulation and tissue repair. We screened recent studies to summarize the advances of the immunomodulatory treatments for periodontitis in the aspects of drug therapy, microbial therapy, stem cell therapy, gene therapy and other therapies. In addition, we included the changes of immune cells and cytokines in the immune microenvironment of periodontitis in the section of drug therapy so as to make it clearer how the treatments took effects accordingly. In the future, more research needs to be done to improve immunotherapy methods and understand the risks and long-term efficacy of these methods in periodontitis.
Avoiding Absolute Quantification Trap: A Novel Predictive Signature of Clinical Benefit to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer
Authors: Liu Chengming , Wang Sihui , Zheng Sufei , Xu Fei , Cao Zheng , Feng Xiaoli , Wang Yan , Xue Qi , Sun Nan , He Jie
Published: November 2021

Immunotherapy has been focused on by many oncologists and researchers. While, due to technical biases of absolute quantification, few traditional biomarkers for anti-PD-1 immunotherapy have been applied in regular clinical practice of non-small cell lung cancer (NSCLC). Therefore, there is an urgent and unmet need for a feasible tool—immune to data source bias—for identifying patients who might benefit from ICIs in clinical practice. Using the strategy based on the relative ranking of gene expression levels, we herein proposed the novel BRGP index (BRGPI): four BRGPs significantly related with progression-free survival of NSCLC patients treated with anti-PD-1 immunotherapy in the multicohort analysis. Moreover, stratification and multivariate Cox regression analyses demonstrated that BRGPI was an independent prognostic factor. Notably, compared to PD-L1, BRGPI exerted the best predictive ability. Further analysis showed that the patients in the BRGPI-low and PD-L1-high subgroup derived more clinical benefits from anti-PD-1 immunotherapy. In conclusion, the prospect of applying the BRGPI to real clinical practice is promising owing to its powerful and reliable predictive value.
Reutilization of Recycled Cellulose Diacetate From Discarded Cigarette Filters in Production of Stone Mastic Asphalt Mixtures
Authors: Liu Huachen , Chen Yikun , Xue Yongjie
Published: November 2021

In this paper, recycled cellulose diacetate (rCDA) derived from cigarette butts was used as a fiber stabilizer to develop stone mastic asphalt (SMA) mixtures. The characterizations of rCDA were investigated by scanning electron microcopy (SEM), a Fourier transform infrared spectrometer (FTIR), and a thermogravimetric analyzer (TGA). Volumetric stability, temperature stability, moisture stability, and fatigue performance of SMA mixtures with rCDA were tested to obtain the pavement performance. Results showed that rCDA appeared to have a tough surface texture with a curly and corrugated structure, which facilitated the enhancement of the cohesion bond with the asphalt binder. TG-DTG indicated that the maximum weight loss (62.48%) obtained at temperatures ranging from 294.1°C to 376.0°C was due to decomposition and degradation of organic matters. When 0.4% rCDA was used in the asphalt mixture, the dynamic stability was 4,105 cycles/mm. The ultimate flexural strength and flexural stiffness modulus were 3,722 MPa and 9.7 MPa. It indicated that the temperature stability of 0.4% rCDA was superior to 0.3% polyacrylonitrile fiber (PAN), while inferior to 0.3% polyester (PET). The value of tensile strength ratio and residual Marshall stability were 80.2 and 75.3%, respectively. The fatigue life of 0.4% rCDA was technically like that of 0.3% PAN and 0.3% PET at lower stress levels. All results concluded that the optimum content of rCDA in asphalt mixtures was 0.4% by mass of the binder.
Deciphering CHFR Role in Pancreatic Ductal Adenocarcinoma
Authors: González-Borja Iranzu , Alors-Pérez Emilia , Amat Irene , Alonso Laura , Viyuela-García Cristina , Goñi Saioa , Reyes José C. , Ceballos-Chávez María , Hernández-García Irene , Sánchez-Frías Marina E. , Santamaría Enrique , Razquin Socorro , Arjona-Sánchez Álvaro , Arrazubi Virginia , Pérez-Sanz Jairo , Vera Ruth , Fernández-Irigoyen Joaquín , Castaño Justo P. , Viúdez Antonio
Published: November 2021

Checkpoint with forkhead-associated and ring finger domains (CHFR) has been proposed as a predictive and prognosis biomarker for different tumor types, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study was two-pronged: to review the role of CHFR in PDAC and evaluating CHFR as a potential predictive biomarker in this disease. For this purpose, we first explored the CHFR messenger (m)RNA expression and promoter methylation through the TCGA database. Secondly, the CHFR expression and promoter methylation were prospectively evaluated in a cohort of patients diagnosed with borderline (n = 19) or resectable (n = 16) PDAC by immunohistochemistry (IHC), methylation specific-PCR (MSP), and pyrosequencing. The results from the TCGA database showed significant differences in terms of progression-free survival (PFS) and overall survival (OS) based on the CHFR mRNA expression, which was likely independent from the promoter methylation. Importantly, our results showed that in primarily resected patients and also the entire cohort, a higher CHFR expression as indicated by the higher IHC staining intensity might identify patients with longer disease-free survival (DFS) and OS, respectively. Similarly, in the same cohorts, patients with lower methylation levels by pyrosequencing showed significantly longer OS than patients without this pattern. Both, the CHFR expression intensity and its promoter methylation were established as independent prognostic factors for PFS and OS in the entire cohort. In contrast, no significant differences were found between different methylation patterns for CHFR and the response to taxane-based neoadjuvant treatment. These results suggest the potential role of the higher expression of CHFR and the methylation pattern of its promoter as potential prognostic biomarkers in PDAC, thus warranting further comprehensive studies to extend and confirm our preliminary findings.
Extracorporeal Cytokine Removal in Critically Ill COVID-19 Patients: A Case Series
Authors: Virág Marcell , Rottler Máté , Ocskay Klementina , Leiner Tamás , Horváth Balázs , Blanco Daniel Adam , Vasquez Alexa , Bucsi László , Sárkány Ágnes , Molnár Zsolt
Published: November 2021

Introduction: Extracorporeal hemoadsorption (HA) is a potential adjunctive therapy in severe cases of COVID-19 associated pneumonia. In this retrospective study we report data from critically ill patients treated with HA during the first and second wave of the pandemic.

Patients and Methods: All patients, who received HA therapy with CytoSorb within the first 96 h of intensive care unit (ICU) admission without hospital-acquired bacterial superinfection, were included. Clinical and laboratory data were collected: on admission, before (TB) and after (TA) HA therapy.

Results: Out of the 367 COVID-19 cases, 13 patients were treated with CytoSorb, also requiring mechanical ventilation and renal replacement therapy. All patients were alive at the end of HA, but only 3 survived hospital stay. From TB-TA there was a tendency of decreasing norepinephrine requirement: 193.7 [IQR: 34.8–270.4] to 50.2 [6.5–243.5] ug/kg/day and increasing PaO2/FiO2 ratio 127.8 (95% CI: 96.0–159.6) to 155.0 (115.3–194.6) mmHg but they did not reach statistical significance (p = 0.14 and 0.58, respectively). Treatment related adverse events were not reported.

Conclusion: The treatment was well-tolerated, and there was a tendency toward an improvement in vasopressor need and oxygenation during the course of HA. These observations render the need for prospective randomized trials.
Community-Acquired Respiratory Distress Syndrome Toxin: Unique Exotoxin for M. pneumoniae
Authors: Su Xiaoling , You Xiaoxing , Luo Haodang , Liang Keying , Chen Li , Tian Wei , Ye Zufeng , He Jun
Published: November 2021

Mycoplasma pneumoniae infection often causes respiratory diseases in humans, particularly in children and adults with atypical pneumonia and community-acquired pneumonia (CAP), and is often exacerbated by co-infection with other lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disorder. Community-acquired respiratory distress syndrome toxin (CARDS TX) is the only exotoxin produced by M. pneumoniae and has been extensively studied for its ADP-ribosyltransferase (ADPRT) activity and cellular vacuolization properties. Additionally, CARDS TX induces inflammatory responses, resulting in cell swelling, nuclear lysis, mucus proliferation, and cell vacuolization. CARDS TX enters host cells by binding to the host receptor and is then reverse transported to the endoplasmic reticulum to exert its pathogenic effects. In this review, we focus on the structural characteristics, functional activity, distribution and receptors, mechanism of cell entry, and inflammatory response of CARDS TX was examined. Overall, the findings of this review provide a theoretical basis for further investigation of the mechanism of M. pneumoniae infection and the development of clinical diagnosis and vaccines.
Interplay of Trans- and Cis-Interactions of Glycolipids in Membrane Adhesion
Authors: Kav Batuhan , Demé Bruno , Gege Christian , Tanaka Motomu , Schneck Emanuel , Weikl Thomas R.
Published: November 2021

Glycolipids mediate stable membrane adhesion of potential biological relevance. In this article, we investigate the trans- and cis-interactions of glycolipids in molecular dynamics simulations and relate these interactions to the glycolipid-induced average separations of membranes obtained from neutron scattering experiments. We find that the cis-interactions between glycolipids in the same membrane leaflet tend to strengthen the trans-interactions between glycolipids in apposing leaflets. The trans-interactions of the glycolipids in our simulations require local membrane separations that are significantly smaller than the average membrane separations in the neutron scattering experiments, which indicates an important role of membrane shape fluctuations in glycolipid trans-binding. Simulations at the experimentally measured average membrane separations provide a molecular picture of the interplay between glycolipid attraction and steric repulsion of the fluctuating membranes probed in the experiments.
Recent High-Resolution Structures of Amyloids Involved in Neurodegenerative Diseases
Authors: Diaz-Espinoza Rodrigo
Published: November 2021

Amyloids are highly ordered aggregates composed of proteins or peptides. They are involved in several pathologies, including hallmark neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD). Individuals affected by these diseases accumulate in their brains amyloids inclusions composed of misfolded forms of a peptide (Aβ) and a protein (Tau) in AD and α-synuclein protein (α-Sn) in PD. Tau and α-Sn aggregates are also present in other neurodegenerative diseases. The insoluble nature and heterogeneity of amyloids have hampered their study at the molecular level. However, the use of solid state NMR and Cryogenic-electron microscopy along with fine-tuned modulation of the aggregation in vitro and improved isolation methods of brain-derived amyloids has allowed the elucidation of these elusive conformations at high resolution. In this work, we review the latest progress on the recent amyloid structures reported for Aβ, Tau, and α-Sn. The two-fold symmetry emerges as a convergent feature in the tridimensional arrangement of the protofilaments in the fibrillary structure of these pathological amyloids, with many of them exhibiting a Greek-key topology as part of their overall architecture. These specific features can serve as novel guides to seek potential molecular targets in drug design efforts.
Time in Brain: How Biological Rhythms Impact on EEG Signals and on EEG-Derived Brain Networks
Authors: Lehnertz Klaus , Rings Thorsten , Bröhl Timo
Published: November 2021

Electroencephalography (EEG) is a widely employed tool for exploring brain dynamics and is used extensively in various domains, ranging from clinical diagnosis via neuroscience, cognitive science, cognitive psychology, psychophysiology, neuromarketing, neurolinguistics, and pharmacology to research on brain computer interfaces. EEG is the only technique that enables the continuous recording of brain dynamics over periods of time that range from a few seconds to hours and days and beyond. When taking long-term recordings, various endogenous and exogenous biological rhythms may impinge on characteristics of EEG signals. While the impact of the circadian rhythm and of ultradian rhythms on spectral characteristics of EEG signals has been investigated for more than half a century, only little is known on how biological rhythms influence characteristics of brain dynamics assessed with modern EEG analysis techniques. At the example of multiday, multichannel non-invasive and invasive EEG recordings, we here discuss the impact of biological rhythms on temporal changes of various characteristics of human brain dynamics: higher-order statistical moments and interaction properties of multichannel EEG signals as well as local and global characteristics of EEG-derived evolving functional brain networks. Our findings emphasize the need to take into account the impact of biological rhythms in order to avoid erroneous statements about brain dynamics and about evolving functional brain networks.
Delayed Respiratory Insufficiency and Extramuscular Abnormalities in Selenoprotein N-Related Myopathies
Authors: Zhang Shu , Lei Lin , Fan Zhirong , Su Shengyao , Duo Jianying , Luan Qinrong , Lu Yan , Di Li , Wang Min , Da Yuwei
Published: November 2021

Background: Selenoprotein N-related myopathies (SEPN1-RMs) are a subset of congenital myopathies caused by mutations of Selenoprotein N gene (SELENON or SEPN1). Clinical phenotype is considered as highly consistent and little attention has been given to the extramuscular abnormalities.

Methods: We reported clinical, histopathological, and genetic features of four Chinese patients with SEPN1-RM and performed literature review on delayed respiratory insufficiency and extramuscular involvement.

Results: A total of four patients exhibited both the typical and atypical clinical features of SEPN1-RM. The classical manifestations included axial and limb girdle weakness, spinal rigidity, scoliosis, respiratory insufficiency, and multiminicore morphological lesions. However, high interindividual variability was noticed on disease severity, especially the onset of respiratory involvement. Two adult patients postponed respiratory insufficiency to the third decade of life, while two juvenile patients manifested early hypoventilation with puberty exacerbation. As atypical features, extramuscular involvement of weight gain, subcutaneous adipose tissue accumulation, intellectual disability, and mild cardiac changes were observed. Molecular findings revealed three novel mutations of SELENON such as c.1286_1288 del CCT, c.1078_1086dupGGCTACATA, and c.785 G>C. Ten cases with delayed respiratory insufficiency were identified from previous publications. A total of 18 studies described extramuscular abnormalities including joint contractures, alterations of body mass index (BMI), mild cardiac changes, and insulin resistance. Intellectual impairment was extremely rare.

Conclusion: SEPN1-RM should be considered as a differential diagnosis in adult patients with delayed respiratory involvement. Extramuscular involvement such as body composition alterations deserves more clinical attention. The novel mutations of SELENON widened the genetic spectrum of patients with SEPN1-RM.
Minimal Access (Endoscopic and Robotic) Breast Surgery in the Surgical Treatment of Early Breast Cancer—Trend and Clinical Outcome From a Single-Surgeon Experience Over 10 Years
Authors: Lai Hung-Wen , Chen Shou-Tung , Lin Ying-Jen , Lin Shih-Lung , Lin Ching-Min , Chen Dar-Ren , Kuo Shou-Jen
Published: November 2021

Objective

Endoscopic assisted breast surgery (EABS) or robotic assisted breast surgery (RABS) performed through minimal axillary and/or peri-areolar incisions has become the representative of minimal access breast surgery (MABS). We report the trend and clinical outcome of MABS for treatment of breast cancer.

Methods

Information on patients who underwent breast cancer operation by the principal investigator during the period of 2011 to 2020 was collected from a single institute for analysis. The clinical outcome, trend, and cost of MABS were analyzed and compared with conventional breast surgery (CBS).

Results

A total of 824 breast cancer patients operated by a single surgeon were enrolled in this study: 254 received CBS and 570 received MABS, namely, 476 EABS and 94 RABS. From 2011 to 2020, the number of MABS performed annually has shown an increasing trend. Compared with CBS, MABS such as breast conserving surgery and nipple sparing mastectomy (NSM) have effectively reduced wound scar length. Since the sequential uprise from conventional NSM (C-NSM), dual-axillary-areolar-incision two dimensional (2D) endoscopic assisted NSM (E-NSM), single-axillary-incision E-NSM, robotic assisted NSM (R-NSM), and single-port 3D E-NSM, the development of minimal access mastectomies increasingly paralleled with NSM. The operation time of various MABS decreased significantly and showed no statistical difference compared with CBS. R-NSM was associated with highest cost, followed by 3D E-NSM, E-NSM, and C-NSM. The positive surgical margin rate and local recurrence rate of MABS and CBS were not statistically different.

Conclusion

MABS showed comparable clinical outcome and preliminary oncologic safety as CBS and has been increasingly performed as the surgical treatment of breast cancer, especially minimal access NSM.
Downstaging Therapies for Unresectable Hepatocellular Carcinoma Prior to Hepatic Resection: A Systematic Review and Meta-Analysis
Authors: Chen Xinyu , Lai Lin , Ye Jiazhou , Li Lequn
Published: November 2021

Introduction

Hepatocellular carcinoma (HCC) is a high-grade malignant disease with unfavorable prognosis, and although surgical therapy is necessary, not all patients with HCC are suitable candidates for surgery. Downstaging as preoperative therapeutic strategy, which can convert unresectable HCC into resectable HCC, intends to increase the resection rate and improve prognosis.

Methods

We searched multiple databases updated to December 30, 2020, for studies on transcatheter arterial chemoembolization (TACE), Yttrium 90 microsphere selective internal radiation (SIR)/transcatheter radioembolization (TARE), hepatic arterial infusion (HAI), and systemic treatment as downstaging treatment before resection for patients with unresectable HCC.

Results

A total of 20 comparative and non-comparative studies were finally included in the meta-analysis. The pooled downstaging rate of hepatic resection (HR) was 14% [95% confidence interval (CI) 0.10–0.17] with significant heterogeneity (I2 = 94.51%). The chemotherapy, combination, and non-cirrhosis groups exhibit higher rates of downstaging, but these differences were not significant. For comparative studies, the overall survival (OS) rates of resection after downstaging were far better than those inpatients who received locoregional therapy (LRT) or systemic treatment alone at 1 year (RR 1.87, 95% CI 1.48–2.38), 3 years (RR 5.56, 95% CI 2.55–12.10), and 5 years (RR 5.47, 95% CI 2.22–13.49). In addition, the pooled disease-free survival (DFS) rates in patients undergoing HR after successful downstaging were 78% (95% CI 0.62–0.93) at 1 year, 47% (95% CI 0.25–0.68) at 3 years, and 46% (95% CI 0.32–0.59) at 5 years. The pooled OS rates were 88% (95% CI 0.82–0.95) at 1 year, 64% (95% CI 0.59–0.69) at 3 years, and 42% (95% CI 0.29–0.54) at 5 years.

Conclusions

Downstaging may serve as a screening tool to identify patients who might benefit from surgery. Resection after successful downstaging can improve prognosis.
Long Non-Coding RNA CCAT2 Activates RAB14 and Acts as an Oncogene in Colorectal Cancer
Authors: Wang Dalu , Li Zhilong , Yin Hongzhuan
Published: November 2021

Here, we investigated the clinicopathological and prognostic potential of the long noncoding RNA Colon Cancer-Associated Transcript 2 (CCAT2) in human colorectal cancer (CRC). We used qPCR to quantify CCAT2 levels in 44 pairs of CRC tissues and adjacent nontumor and healthy colon mucosa tissues, and in several CRC cell lines (SW620, SW480, HT-29, LOVO, HCT116 and DLD-1) and normal human colorectal epithelial cells (HFC). We assessed the effects of CCAT2 overexpression or knockdown on the proliferation, migration and invasion by SW620 and LOVO cells using CCK-8, transwell, and wound−healing assays, respectively. We also investigated the potential interaction between CCAT2 and TAF15 through RNA pull down and rescue experiments. Lastly, we evaluated the expression of the cell cycle progression markers and GSK3β signaling pathway proteins using Western blotting. Our results showed that CCAT2 was upregulated in CRC tissues and cell lines as com-pared to controls. Ectopic expression of CCAT2 promoted CRC cell proliferation, migration and invasion, likely through direct interaction with TAF15, transcriptional activation of RAB14, and activation of the AKT/GSK3β signaling pathway. In vivo, CCAT2 promoted CRC cell growth and metastasis in nude mice. Taken together, these results highlight the actions of CCAT2 as a CRC oncogene.
A New Risk Score Based on Eight Hepatocellular Carcinoma- Immune Gene Expression Can Predict the Prognosis of the Patients
Authors: Ye Dingde , Liu Yaping , Li Guoqiang , Sun Beicheng , Peng Jin , Xu Qingxiang
Published: November 2021

Background

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high morbidity and mortality worldwide. Immunotherapy has emerged as an increasingly important cancer treatment modality. However, the potential relationship between immune genes and HCC still needs to be explored. The purpose of this study is to construct a new prognostic risk signature to predict the prognosis of HCC patients based on the expression of immune-related genes (IRGs) and explore its potential mechanism.

Methods

We analyzed the gene expression data of 332 HCC patient samples and 46 adjacent normal tissues samples (Solid Tissue Normal including cirrhotic tissue) in The Cancer Genome Atlas (TCGA) database and clinical characteristics. We analyzed the gene expression data, identified differentially expressed IRGs in HCC tissues, filtered IRGs with prognostic value to construct an IRG signature, and classified patients into high and low gene expression groups based on the expression of IRGs in their tumor tissues. We also investigated the potential molecular mechanisms of IRGs through a bioinformatics approach using Protein-Protein Interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) database analysis and Gene Ontology (GO) database analysis. Differentially expressed IRGs associated with significant clinical outcomes (SIRGs) were identified by univariate Cox regression analysis. An immune-related risk score model (IRRSM) was established based on Lasso Cox regression analysis and multivariate Cox regression analysis. Based on the IRRSM, the immune score of the patients was calculated, and the patients were divided into high-risk and low-risk patients according to the median score, and the differences in survival between the two groups were compared. Then, the correlation analysis between the IRRSM and clinical characteristics was performed, and the IRRSM was validated using the International Cancer Genome Consortium (ICGC) database.

Results

The IRRSM was eventually constructed and confirmed to be an independent prognostic model for HCC patients. The IRRSM was shown to be positively correlated with the infiltration of four types of immune cells.

Conclusion

Our results showed that some SIRGs have potential value for predicting the prognosis and clinical outcomes of HCC patients. IRGs affect the prognosis of HCC patients by regulating the tumor immune microenvironment (TIME). This study provides a new insight for immune research and treatment strategies in HCC patients.
A Hypoxia-Related Long Non-Coding RNAs Signature Associated With Prognosis in Lower-Grade Glioma
Authors: Feng Qinglin , Qian Cheng , Fan Shibing
Published: November 2021

Accumulating evidence suggests that hypoxia microenvironment and long non-coding lncRNAs (lncRNAs) exert critical roles in tumor development. Herein, we aim to develop a hypoxia-related lncRNA (HRL) model to predict the survival outcomes of patient with lower-grade glioma (LGG). The RNA-sequencing data of 505 LGG samples were acquired from The Cancer Genome Atlas (TCGA). Using consensus clustering based on the expression of hypoxia-related mRNAs, these samples were divided into three subsets that exhibit distinct hypoxia content, clinicopathologic features, and survival status. The differentially expressed lncRNAs across the subgroups were documented as candidate HRLs. With LASSO regression analysis, eight informative lncRNAs were selected for constructing the prognostic HRL model. This signature had a good performance in predicting LGG patients’ overall survival in the TCGA cohort, and similar results could be achieved in two validation cohorts from the Chinese Glioma Genome Atlas. The HRL model also showed correlations with important clinicopathologic characteristics such as patients’ age, tumor grade, IDH mutation, 1p/19q codeletion, MGMT methylation, and tumor progression risk. Functional enrichment analysis indicated that the HLR signature was mainly involved in regulation of inflammatory response, complement, hypoxia, Kras signaling, and apical junction. More importantly, the signature was related to immune cell infiltration, estimated immune score, tumor mutation burden, neoantigen load, and expressions of immune checkpoints and immunosuppressive cytokines. Finally, a nomogram was developed by integrating the HRL signature and clinicopathologic features, with a concordance index of 0.852 to estimate the survival probability of LGG patients. In conclusion, our study established an effective HRL model for prognosis assessment of LGG patients, which may provide insights for future research and facilitate the designing of individualized treatment.
Radiomics Analysis of Contrast-Enhanced CT for the Preoperative Prediction of Microvascular Invasion in Mass-Forming Intrahepatic Cholangiocarcinoma
Authors: Xiang Fei , Wei Shumei , Liu Xingyu , Liang Xiaoyuan , Yang Lili , Yan Sheng
Published: November 2021

Background

Microvascular invasion (MVI) has been shown to be closely associated with postoperative recurrence and metastasis in patients with intrahepatic cholangiocarcinoma (ICC). We aimed to develop a radiomics prediction model based on contrast-enhanced CT (CECT) to distinguish MVI in patients with mass-forming ICC.

Methods

157 patients were included and randomly divided into training (n=110) and test (n=47) datasets. Radiomic signatures were built based on the recursive feature elimination support vector machine (Rfe-SVM) algorithm. Significant clinical-radiologic factors were screened, and a clinical model was built by multivariate logistic regression. A nomogram was developed by integrating radiomics signature and the significant clinical risk factors.

Results

The portal phase image radiomics signature with 6 features was constructed and provided an area under the receiver operating characteristic curve (AUC) of 0.804 in the training and 0.769 in the test datasets. Three significant predictors, including satellite nodules (odds ratio [OR]=13.73), arterial hypo-enhancement (OR=4.31), and tumor contour (OR=4.99), were identified by multivariate analysis. The clinical model using these predictors exhibited an AUC of 0.822 in the training and 0.756 in the test datasets. The nomogram combining significant clinical factors and radiomics signature achieved satisfactory prediction efficacy, showing an AUC of 0.886 in the training and 0.80 in the test datasets.

Conclusions

Both CECT radiomics analysis and radiologic factors have the potential for MVI prediction in mass-forming ICC patients. The nomogram can further improve the prediction efficacy.
Antibiotic Resistance Pattern of Staphylococcus Aureus Isolated From Pediatrics With Ocular Infections: A 6-Year Hospital-Based Study in China
Authors: Zheng Xiao-Yu , Choy Bonnie Nga Kwan , Zhou Ming-Ming , Zhao Zheng-Yan
Published: November 2021

Staphylococcus aureus (S. aureus) is an important pathogen of ocular infections in pediatrics. The study aimed to identify the prevalence and resistance pattern of S. aureus, especially methicillin-resistant S. aureus (MRSA), in Chinese children with ocular infections. All patients with S. aureus infections were reviewed at a tertiary children's hospital during 2015–2020, and those with ocular infections were investigated for susceptibility results. Of 1,668 S. aureus strains, there were 177 unique isolates from ocular infection. Among them, 45 (25.4%) were MRSA and 132 (74.6%) were methicillin-sensitive S. aureus (MSSA). The proportion of MRSA did not change over time. Most of the strains were obtained from the neonate ward and ophthalmology department (n = 88, 49.7%, and n = 85, 48.0%, respectively), while eye secretion and pus were the main specimen types (n = 128, 72.3%, and n = 37, 20.9%, respectively). MRSA was significantly resistant against penicillin class (97.8%), erythromycin (71.1%), clindamycin (71.1%), and tetracycline (32.1%), with a high multidrug resistance (MDR) rate of 71.1%. However, MRSA was highly sensitive to levofloxacin. Resistance rates against erythromycin and ciprofloxacin as well as MDR percentage all increased among MSSA in children above 1 year of age, ophthalmology department, and outpatient population and decreased in eye secretion specimen. The mean resistance percentage remained stable for MRSA and MSSA during the study period. The survey of ocular S. aureus pathogens in pediatrics and their antibiotic resistance patterns helps in clinical treatment. MRSA with many strains demonstrating MDR is highly prevalent in children with ocular infections in Southeast China. Levofloxacin is an effective topical antibiotic for ocular MRSA infection, while erythromycin has a high resistance rate. The antibiotic resistance patterns of MRSA and MSSA differs and varies by different stratifications. A cautious use of antibiotics should be considered.
Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population
Authors: Zhou Wei , Cai Heng , Li Huizhong , Ji Zhe , Gu Maosheng
Published: November 2021

Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.

Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.

Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.

Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.
Remimazolam Protects Against LPS-Induced Endotoxicity Improving Survival of Endotoxemia Mice
Authors: Liu Xiaolei , Lin Shaoping , Zhong Yiyue , Shen Jiaojiao , Zhang Xuedi , Luo Shuhua , Huang Li , Zhang Liangqing , Zhou Shuangnan , Tang Jing
Published: November 2021

Remimazolam is a new benzodiazepine of sedative drugs with an ultra-short-acting anesthetic effect, commonly used for critically ill patients (especially septic patients) in intensive care units (ICUs). Although some anesthetics have been reported to show certain anti-inflammatory effects, the role of remimazolam in inflammation is still remained unknown. Here, we studied the effects of remimazolam on macrophage in response to LPS both in vivo and in vitro. Interestingly, compared with LPS treatment group, remimazolam remarkably improved survival rate of endotoxemia mice and decreased the release of LPS-induced inflammatory mediators (such as TNF-α, IL-6, and IL-1β). We further found that remimazolam not only inhibited the activation of MAPK signal pathway at 15 min after LPS treatment but also disturbed Rab5a related TLR4 expression at cell surface in response to LPS at a later time. Such evidence suggests that remimazolam might be beneficial to septic patients who are suffering from uncontrolled inflammatory responses.
Hypoxia Induces Renal Epithelial Injury and Activates Fibrotic Signaling Through Up-Regulation of Arginase-II
Authors: Liang Xiujie , Potenza Duilio Michele , Brenna Andrea , Ma Yiqiong , Ren Zhilong , Cheng Xin , Ming Xiu-Fen , Yang Zhihong
Published: November 2021

The ureohydrolase, type-II arginase (Arg-II), is a mitochondrial enzyme metabolizing L-arginine into urea and L-ornithine and is highly expressed in renal proximal tubular cells (PTC) and upregulated by renal ischemia. Recent studies reported contradictory results on the role of Arg-II in renal injury. The aim of our study is to investigate the function of Arg-II in renal epithelial cell damage under hypoxic conditions. Human renal epithelial cell line HK2 was cultured under hypoxic conditions for 12–48 h. Moreover, ex vivo experiments with isolated kidneys from wild-type (WT) and genetic Arg-II deficient mice (Arg-II–/–) were conducted under normoxic and hypoxic conditions. The results show that hypoxia upregulates Arg-II expression in HK2 cells, which is inhibited by silencing both hypoxia-inducible factors (HIFs) HIF1α and HIF2α. Treatment of the cells with dimethyloxaloylglycine (DMOG) to stabilize HIFα also enhances Arg-II. Interestingly, hypoxia or DMOG upregulates transforming growth factor β1 (TGFβ1) levels and collagens Iα1, which is prevented by Arg-II silencing, while TGFβ1-induced collagen Iα1 expression is not affected by Arg-II silencing. Inhibition of mitochondrial complex-I by rotenone abolishes hypoxia-induced reactive oxygen species (mtROS) and TGFβ1 elevation in the cells. Ex vivo experiments show elevated Arg-II and TGFβ1 expression and the injury marker NGAL in the WT mouse kidneys under hypoxic conditions, which is prevented in the Arg-II–/– mice. Taking together, the results demonstrate that hypoxia activates renal epithelial HIFs-Arg-II-mtROS-TGFβ1-cascade, participating in hypoxia-associated renal injury and fibrosis.
Non-invasive Metabolomic Profiling of Embryo Culture Medium Using Raman Spectroscopy With Deep Learning Model Predicts the Blastocyst Development Potential of Embryos
Authors: Zheng Wei , Zhang Shuoping , Gu Yifan , Gong Fei , Kong Lingyin , Lu Guangxiu , Lin Ge , Liang Bo , Hu Liang
Published: November 2021

Purpose: This study aimed to establish a non-invasive predicting model via Raman spectroscopy for evaluating the blastocyst development potential of day 3 high-quality cleavage stage embryos.

Methods: Raman spectroscopy was used to detect the metabolic spectrum of spent day 3 (D3) embryo culture medium, and a classification model based on deep learning was established to differentiate between embryos that could develop into blastocysts (blastula) and that could not (non-blastula). The full-spectrum data for 80 blastula and 48 non-blastula samples with known blastocyst development potential from 34 patients were collected for this study.

Results: The accuracy of the predicting method was 73.53% and the main different Raman shifts between blastula and non-blastula groups were 863.5, 959.5, 1,008, 1,104, 1,200, 1,360, 1,408, and 1,632 cm–1 from 80 blastula and 48 non-blastula samples by the linear discriminant method.

Conclusion: This study demonstrated that the developing potential of D3 cleavage stage embryos to the blastocyst stage could be predicted with spent D3 embryo culture medium using Raman spectroscopy with deep learning classification models, and the overall accuracy reached at 73.53%. In the Raman spectroscopy, ribose vibration specific to RNA were found, indicating that the difference between the blastula and non-blastula samples could be due to materials that have similar structure with RNA. This result could be used as a guide for biomarker development of embryo quality assessment in the future.
Evolution of Rosaceae Plastomes Highlights Unique Cerasus Diversification and Independent Origins of Fruiting Cherry
Authors: Zhang Jing , Wang Yan , Chen Tao , Chen Qing , Wang Lei , Liu Zhen-shan , Wang Hao , Xie Rui , He Wen , Li Ming , Liu Cong-li , Yang Shao-feng , Li Meng-yao , Lin Yuan-xiu , Zhang Yun-ting , Zhang Yong , Luo Ya , Tang Hao-ru , Gao Li-zhi , Wang Xiao-rong
Published: November 2021

Rosaceae comprises numerous types of economically important fruits, ornamentals, and timber. The lack of plastome characteristics has blocked our understanding of the evolution of plastome and plastid genes of Rosaceae crops. Using comparative genomics and phylogenomics, we analyzed 121 Rosaceae plastomes of 54 taxa from 13 genera, predominantly including Cerasus (true cherry) and its relatives. To our knowledge, we generated the first comprehensive map of genomic variation across Rosaceae plastomes. Contraction/expansion of inverted repeat regions and sequence losses of the two single-copy regions underlie large genomic variations in size among Rosaceae plastomes. Plastid protein-coding genes were characterized with a high proportion (over 50%) of synonymous variants and insertion-deletions with multiple triplets. Five photosynthesis-related genes were specially selected in perennial woody trees. Comparative genomic analyses implied divergent evolutionary patterns between pomaceous and drupaceous trees. Across all examined plastomes, unique and divergent evolution was detected in Cerasus plastomes. Phylogenomic analyses and molecular dating highlighted the relatively distant phylogenetic relationship between Cerasus and relatives (Microcerasus, Amygdalus, Prunus, and Armeniaca), which strongly supported treating the monophyletic true cherry group as a separate genus excluding dwarf cherry. High genetic differentiation and distinct phylogenetic relationships implied independent origins and domestication between fruiting cherries, particularly between Prunus pseudocerasus (Cerasus pseudocerasus) and P. avium (C. avium). Well-resolved maternal phylogeny suggested that cultivated P. pseudocerasus originated from Longmenshan Fault zone, the eastern edge of Himalaya-Hengduan Mountains, where it was subjected to frequent genomic introgression between its presumed wild ancestors and relatives.
Integrated de novo Analysis of Transcriptional and Metabolic Variations in Salt-Treated Solenostemma argel Desert Plants
Authors: Ahmad Hasan , Maher Mohamed , Abdel-Salam Eslam M. , Li Yufei , Yang Chenkun , ElSafty Nagwa , Ewas Mohamed , Nishawy Elsayed , Luo Jie
Published: November 2021

Solenostemma argel (Delile) Hayne is a desert plant that survives harsh environmental conditions with several vital medicinal properties. Salt stress is a major constraint limiting agricultural production around the globe. However, response mechanisms behind the adaptation of S. argel plants to salt stress are still poorly understood. In the current study, we applied an omics approach to explore how this plant adapts to salt stress by integrating transcriptomic and metabolomic changes in the roots and leaves of S. argel plants under salt stress. De novo assembly of transcriptome produced 57,796 unigenes represented by 165,147 transcripts/isoforms. A total of 730 differentially expressed genes (DEGs) were identified in the roots (396 and 334 were up- and down-regulated, respectively). In the leaves, 927 DEGs were identified (601 and 326 were up- and down-regulated, respectively). Gene ontology and Kyoto Encyclopedia of Genes And Genomes pathway enrichment analyses revealed that several defense-related biological processes, such as response to osmotic and oxidative stress, hormonal signal transduction, mitogen-activated protein kinase signaling, and phenylpropanoid biosynthesis pathways are the potential mechanisms involved in the tolerance of S. argel plants to salt stress. Furthermore, liquid chromatography-tandem mass spectrometry was used to detect the metabolic variations of the leaves and roots of S. argel under control and salt stress. 45 and 56 critical metabolites showed changes in their levels in the stressed roots and leaves, respectively; there were 20 metabolites in common between the roots and leaves. Differentially accumulated metabolites included amino acids, polyamines, hydroxycinnamic acids, monolignols, flavonoids, and saccharides that improve antioxidant ability and osmotic adjustment of S. argel plants under salt stress. The results present insights into potential salt response mechanisms in S. argel desert plants and increase the knowledge in order to generate more tolerant crops to salt stress.
Quantitative Proteomics and Transcriptomics Reveals Differences in Proteins During Anthers Development in Oryza longistaminata
Authors: Sun Yue , Wang Xin , Chen Zhongkai , Qin Lu , Li Bai , Ouyang Linjuan , Peng Xiaosong , He Haohua
Published: November 2021

Oryza longistaminata is an African wild rice species that possesses special traits for breeding applications. Self-incompatibility is the main cause of sterility in O. longistaminata, but here we demonstrated that its pollen vitality are normal. Lipid and carbohydrate metabolism were active throughout pollen development. In this study, we used I2-KI staining and TTC staining to investigate pollen viability. Aniline-blue-stained semithin sections were used to investigate important stages of pollen development. Tandem mass tags (TMT)-based quantitative analysis was used to investigate the profiles of proteins related to lipid and carbohydrate metabolism in 4-, 6-, and 8.5-mm O. longistaminata spikelets before flowering. Pollen was found to germinate normally in vitro and in vivo. We documented cytological changes throughout important stages of anther development, including changes in reproductive cells as they formed mature pollen grains through meiosis and mitosis. A total of 31,987 RNA transcripts and 8,753 proteins were identified, and 6,842 of the proteins could be quantified. RNA-seq and proteome association analysis indicated that fatty acids were converted to sucrose after the 6-mm spikelet stage, based on the abundance of most key enzymes of the glyoxylate cycle and gluconeogenesis. The abundance of proteins involved in pollen energy metabolism was further confirmed by combining quantitative real-time PCR with parallel reaction monitoring (PRM) analyses. In conclusion, our study provides novel insights into the pollen viability of O. longistaminata at the proteome level, which can be used to improve the efficiency of male parent pollination in hybrid rice breeding applications.