Publications by authors named "Bo Gao"

906 Publications

Intracardiac, pulmonary cement embolism in a 67-year-old female after cement-augmented pedicle screw instrumentation: A case report and review of literature.

World J Clin Cases 2021 May;9(13):3120-3129

Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510289, Guangdong Province, China.

Background: We report a case of Intracardiac, pulmonary, and intravenous cement embolism after cement-augmented pedicle screw instrumentation in treating spondylolisthesis underlying osteoporotic bone, which was successfully managed by conservative treatment. We describe the treatment and outcome of the patient, hoping to shed light on the management of bone cement embolism.

Case Summary: A 67-year-old female suffered from progressive low back pain and numbness in lower extremities for 30 years. She was diagnosed with L4 and L5 spondylolisthesis, spinal stenosis, and osteoporosis. The patient underwent spinal canal decompression, an interbody fusion of L4/5 and L5/S1, cement-augmented pedicle screw instrumentation in L4-L5 segments, and regular pedicle screw in S1 segments. Three days postoperatively, a sudden drop in oxygen saturation occurred. Computerized tomography scan confirmed Intracardiac, pulmonary, and intravenous embolism. The patient was treated conservatively by continuous low-flow oxygen inhalation, anti-coagulation, and antibiotic therapy for 1 mo and continued anticoagulation treatment for 6 mo. The patient showed no further symptoms in a 30-mo follow-up.

Conclusion: Intracardiac, pulmonary cement embolism after cement-augmented pedicle screw instrumentation is extremely rare. Careful clinical and radiographic evaluation is required in multiple sites of bone cement embolism. Conservative treatment may be a primary consideration in scattered emboli without life-threatening conditions, but a clinical decision should be made on an individualized basis.
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http://dx.doi.org/10.12998/wjcc.v9.i13.3120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080748PMC
May 2021

Coupling SnS and rGO aerogel to CuS for enhanced light-assisted OER electrocatalysis.

Dalton Trans 2021 Apr;50(16):5530-5539

School of Materials Science and Engineering, Liaocheng University, Shandong, 252059, China.

In order to harvest more light wavelengths to improve the light-assisted electrochemical water splitting capacity, we developed a novel heterostructure of three-dimensional (3D) flower-like CuS architecture with accompanying SnS2 nanoparticles and reduced graphene oxide (rGO) aerogel for outstanding light-assisted electrocatalytic OER performance and good stability. The excellent catalytic kinetics, effective capturing of visible light, and rapid charge transfer of the CuS/SnS2/rGO (CSr) heterostructure were demonstrated. The overpotential (264 mV@10 mA cm-2) under light-assisted conditions is 20% lower than that under light-chopped conditions. SnS2 can harvest more light wavelengths and this boosts its intrinsic activity. However, with the increase of the SnS2 content, the OER activity decreases. The combination of the CS heterostructure and the rGO conductive aerogel achieves rapid charge transfer. Furthermore, the possible mechanism of the light-assisted electrocatalytic OER was also proposed. Overall, this work provides new insights into the simple and scalable fabrication of a highly efficient, low-cost, and stable non-noble-metal-based electrocatalyst.
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http://dx.doi.org/10.1039/d1dt00271fDOI Listing
April 2021

Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538.

Oncoimmunology 2021 Apr 12;10(1):1908771. Epub 2021 Apr 12.

Department of Medical Oncology, Austin Health, Melbourne, Australia.

: Adrenocortical carcinoma is a rare malignancy, with poor prognosis and limited treatment options for patients with advanced disease. Chemotherapy is the current standard first-line treatment, providing only a modest survival benefit. There is only limited treatment experience with immunotherapy using single-agent anti-PD-1/PD-L1 therapy. To date no clinical trials have been reported using combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade in this patient population. : CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Participants received the anti-PD-1 antibody nivolumab (3 mg/kg IV) and the anti-CTLA-4 antibody ipilimumab (1 mg/kg IV) every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. Response was assessed every 12 weeks by RECIST version 1.1. Primary endpoint was clinical benefit rate (complete response, partial response, stable disease at 12 weeks). : Six patients with adrenocortical carcinoma were enrolled and received treatment. Two patients (33%) have an ongoing partial response (10 and 25 months +) and two patients (33%) stable disease leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instable phenotype. One patient rapidly progressed shortly after enrollment into the trial and did not undergo restaging. Immunotherapy-related toxicity was reported in all patients, with four patients (67%) experiencing grade 3/4 hepatitis leading to discontinuation of treatment. : This is the first treatment experience using ipilimumab and nivolumab combination immunotherapy in patients with advanced adrenocortical carcinoma. Durable responses have been observed in a subset of patients suggesting that this treatment regimen should be further investigated in this patient population.
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http://dx.doi.org/10.1080/2162402X.2021.1908771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043165PMC
April 2021

Application of Multilayer Network Models in Bioinformatics.

Front Genet 2021 31;12:664860. Epub 2021 Mar 31.

Department of Radiology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China.

Multilayer networks provide an efficient tool for studying complex systems, and with current, dramatic development of bioinformatics tools and accumulation of data, researchers have applied network concepts to all aspects of research problems in the field of biology. Addressing the combination of multilayer networks and bioinformatics, through summarizing the applications of multilayer network models in bioinformatics, this review classifies applications and presents a summary of the latest results. Among them, we classify the applications of multilayer networks according to the object of study. Furthermore, because of the systemic nature of biology, we classify the subjects into several hierarchical categories, such as cells, tissues, organs, and groups, according to the hierarchical nature of biological composition. On the basis of the complexity of biological systems, we selected brain research for a detailed explanation. We describe the application of multilayer networks and chronological networks in brain research to demonstrate the primary ideas associated with the application of multilayer networks in biological studies. Finally, we mention a quality assessment method focusing on multilayer and single-layer networks as an evaluation method emphasizing network studies.
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http://dx.doi.org/10.3389/fgene.2021.664860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044439PMC
March 2021

Study of complex structural variations of X-linked deafness-2 (DFNX2) based on single-molecule sequencing.

Biosci Rep 2021 Apr 16. Epub 2021 Apr 16.

PLA General Hospital, Beijing, China.

X-linked deafness-2 (DFNX2) is cochlear incomplete partition type III (IP-III), one of inner ear malformations characterized by an abnormally wide opening in the bone separating the basal turn of the cochlea from the internal auditory canal, fixation of the stapes and cerebrospinal fluid (CSF) gusher upon stapedectomy or cochleostomy. The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of X-linked deafness-2 (DFNX2) and compare the efficiency of different sequencing methods, twelve unrelated patients were enrolled in this study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been be due to non-homologous end joining, while non-allelic homologous recombination within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results.
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http://dx.doi.org/10.1042/BSR20203740DOI Listing
April 2021

The value of the Demetics ultrasound-assisted diagnosis system in the differential diagnosis of benign from malignant thyroid nodules and analysis of the influencing factors.

Eur Radiol 2021 Apr 15. Epub 2021 Apr 15.

Department of Ultrasound, Institute of Ultrasound in Musculoskeletal Sports Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510317, Guangdong, People's Republic of China.

Objectives: To evaluate the value of Demetics and to explore whether Demetics can help radiologists with varying years of experience in the differential diagnosis of benign from malignant thyroid nodules.

Methods: The clinical application value of Demetics was assessed by comparing the diagnostic accuracy of radiologists before and after applying Demetics. This retrospective analysis included 284 thyroid nodules that underwent pathological examinations. Two different combined methods were applied. Using method 1: the original TI-RADS classification was forcibly upgraded or downgraded by one level when Demetics classified the thyroid nodules as malignant or benign. Using method 2: the TI-RADS and benign or malignant classification of the thyroid nodules were flexibly adjusted after the physician learned the Demetics' results.

Results: Demetics exhibited a higher sensitivity than did junior radiologist 1 (p = 0.029) and was similar in sensitivity to the two senior radiologists. Demetics had a higher AUC than both junior radiologists (p = 0.042, p = 0.038) and an AUC similar to that of the senior radiologists. The sensitivity (p = 0.035) and AUC (p = 0.031) of junior radiologist 1 and the specificity (p < 0.001) and AUC (p = 0.026) of junior radiologist 2 improved with combined method 1. The AUC of junior radiologist 2 improved with combined method 2 (p = 0.045). The factors influencing the diagnostic results of Demetics include sonographic signs (echogenicity and echogenic foci), contrast of the image, and nodule size.

Conclusion: Demetics exhibited high sensitivity and accuracy in the differential diagnosis of benign from malignant thyroid nodules. Demetics could improve the diagnostic accuracy of junior radiologists.

Key Points: • Demetics exhibited a high sensitivity and accuracy in the differential diagnosis of benign from malignant thyroid nodules. • Demetics could improve the diagnostic accuracy of junior radiologists in the differential diagnosis of benign from malignant thyroid nodules. • Factors influencing the diagnostic results of Demetics include the sonographic signs (echogenicity and echogenic foci), contrast of the image, and nodule size.
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http://dx.doi.org/10.1007/s00330-021-07884-zDOI Listing
April 2021

Opposite Effects of Potassium Ions on the Thermal Stability of i-Motif DNA in Different Buffer Systems.

Authors:
Bo Gao Xi-Miao Hou

ACS Omega 2021 Apr 24;6(13):8976-8985. Epub 2021 Mar 24.

College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.

i-motifs are noncanonical DNA structures formed the stack of intercalating hemi-protonated C: C base pairs in C-rich DNA strands and play essential roles in the regulation of gene expression. Here, we systematically investigated the impacts of K on i-motif DNA folding using different buffer systems. We found that i-motif structures display very different values at the same pH and ion strength in different buffer systems. More importantly, K disrupts the i-motif formed in the MES and Bis-Tris buffer; however, K stabilizes the i-motif in phosphate, citrate, and sodium cacodylate buffers. Next, we selected phosphate buffer and confirmed by single-molecule fluorescence resonance energy transfer that K indeed has the stabilizing effect on the folding of i-motif DNA from pH 5.8 to 8.0. Nonetheless, circular dichroism spectra further indicate that the structures formed by i-motif sequences at high K concentrations at neutral and alkaline pH are not i-motif but other types of higher-order structures and most likely C-hairpins. We finally proposed the mechanisms of how K plays the opposite roles in different buffer systems. The present study may provide new insights into our understanding of the formation and stability of i-motif DNA.
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http://dx.doi.org/10.1021/acsomega.0c06350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028132PMC
April 2021

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study.

Lancet Respir Med 2021 Apr 6. Epub 2021 Apr 6.

University of Chicago, Chicago, IL, USA.

Background: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study.

Methods: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067.

Findings: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation.

Interpretation: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S2213-2600(20)30515-4DOI Listing
April 2021

Immune-Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Synopsis of Response Rates.

Oncologist 2021 Apr 5. Epub 2021 Apr 5.

Blacktown Clinical School, Western Sydney University, Sydney, New South Wales, Australia.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I-IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. IMPLICATIONS FOR PRACTICE: Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.
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http://dx.doi.org/10.1002/onco.13776DOI Listing
April 2021

Advances in the Identification of Circular RNAs and Research Into circRNAs in Human Diseases.

Front Genet 2021 19;12:665233. Epub 2021 Mar 19.

Department of Radiology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) with a closed-loop structure that are mainly produced by variable processing of precursor mRNAs (pre-mRNAs). They are widely present in all eukaryotes and are very stable. Currently, circRNA studies have become a hotspot in RNA research. It has been reported that circRNAs constitute a significant proportion of transcript expression, and some are significantly more abundantly expressed than other transcripts. CircRNAs have regulatory roles in gene expression and critical biological functions in the development of organisms, such as acting as microRNA sponges or as endogenous RNAs and biomarkers. As such, they may have useful functions in the diagnosis and treatment of diseases. CircRNAs have been found to play an important role in the development of several diseases, including atherosclerosis, neurological disorders, diabetes, and cancer. In this paper, we review the status of circRNA research, describe circRNA-related databases and the identification of circRNAs, discuss the role of circRNAs in human diseases such as colon cancer, atherosclerosis, and gastric cancer, and identify remaining research questions related to circRNAs.
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http://dx.doi.org/10.3389/fgene.2021.665233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017306PMC
March 2021

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada.

Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.
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http://dx.doi.org/10.3390/ijms22062839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000060PMC
March 2021

microRNA-23 inhibits inflammation to alleviate rheumatoid arthritis via regulating CXCL12.

Exp Ther Med 2021 May 3;21(5):459. Epub 2021 Mar 3.

Department of Rheumatology and Immunology, The Second Changzhou People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213004, P.R. China.

Rheumatoid arthritis (RA) is a common systemic, inflammatory and autoimmune disorder. MicroRNAs (miRs) are strongly associated with the initiation and progression of RA. However, the functions and mechanisms underlying miR-23 in RA are not completely understood. Therefore, the present study aimed to investigate the molecular mechanisms underlying miR-23 in RA. A bioinformatics tool (StarBase) and a wide range of experimental assays, including reverse transcription-quantitative PCR, western blotting, luciferase reporter assays and ELISAs, were performed to investigate the biological role of miR-23 in RA. The results indicated that miR-23 was downregulated and chemokine C-X-C motif ligand 12 (CXCL12) was upregulated in RA samples compared with healthy samples. Furthermore, miR-23 overexpression suppressed inflammation via reducing TNF-α, IL-1β and IL-8 expression levels compared with the NC mimic group. Regarding the underlying mechanism, compared with NC mimic, miR-23 mimic decreased CXCL12 mRNA expression by binding to its 3'-untranslated region. Additionally, CXCL12 overexpression reversed miR-23 mimic-mediated effects on inflammation. NF-κB signaling is associated with inflammation. Therefore, the present study indicated that CXCL12 promoted inflammation by activating NF-κB signaling. In conclusion, miR-23 inhibited inflammation to alleviate RA by regulating CXCL12 via the NF-κB signaling pathway, which may serve as a potential target for the diagnosis and treatment of RA.
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http://dx.doi.org/10.3892/etm.2021.9890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967800PMC
May 2021

Identification of long noncoding RNAs with machine learning methods: a review.

Brief Funct Genomics 2021 Mar 23. Epub 2021 Mar 23.

Second Affiliated Hospital, Harbin Medical University, Harbin, China.

Long noncoding RNAs (lncRNAs) are noncoding RNAs with a length greater than 200 nucleotides. Studies have shown that they play an important role in many life activities. Dozens of lncRNAs have been characterized to some extent, and they are reported to be related to the development of diseases in a variety of cells. However, the biological functions of most lncRNAs are currently still unclear. Therefore, accurately identifying and predicting lncRNAs would be helpful for research on their biological functions. Due to the disadvantages of high cost and high resource-intensiveness of experimental methods, scientists have developed numerous computational methods to identify and predict lncRNAs in recent years. In this paper, we systematically summarize the machine learning-based lncRNAs prediction tools from several perspectives, and discuss the challenges and prospects for the future work.
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http://dx.doi.org/10.1093/bfgp/elab017DOI Listing
March 2021

Single-cell RNA sequencing analysis identifies key genes in brain metastasis from lung adenocarcinoma.

Curr Gene Ther 2021 Mar 18. Epub 2021 Mar 18.

Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, 150080. China.

Background: Lung adenocarcinoma (LADC) is the most common type of lung cancer and is a subtype of non-small-cell lung cancer (NSCLC). Approximately 40% of LADC patients experience brain metastases (BMs) during the course of the disease. In this study, integrated bioinformatics methods were applied to identify key genes related to brain metastasis in lung adenocarcinoma.

Methods: We derived and characterized genes differentially expressed between the primary tumour and brain metastases using tumour cells isolated from two lung cancer Patient-derived xenografts (PDX) cases (GSE 69405). Gene ontology (GO) and KEGG pathway enrichment analyses were applied, and protein-protein interaction (PPI) networks and Cytoscape software were utilized to identify key genes.

Results: Four key genes including CKAP4 (Cytoskeleton Associated Protein 4), SERPINA1 (Serpin Family A Member 1), SDC2 (Syndecan 2) and GNG11 (G Protein Subunit Gamma 11) were identified for BM-LADC by the Venn diagram.

Conclusion: We believe these key genes may be potential biomarkers for improved prognosis and treatment of lung adenocarcinoma.
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http://dx.doi.org/10.2174/1566523221666210319104752DOI Listing
March 2021

Feasibility and safety of both His bundle pacing and left bundle branch area pacing in atrial fibrillation patients: intermediate term follow-up.

J Interv Card Electrophysiol 2021 Mar 15. Epub 2021 Mar 15.

Department of Cardiology, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, No. 3 Qingchun East Road, Hangzhou, 310016, Zhejiang, People's Republic of China.

Purpose: His bundle pacing (HBP) improves heart failure (HF) in atrial fibrillation (AF) pacing-dependent patients with a potential for a progressively increased threshold. HBP with right ventricular pacing (RVP) as a backup is always the preferred choice; however, RVP may induce HF. His Purkinje system pacing (HPSP) includes HBP and left bundle branch area pacing (LBBAP). LBBAP maintains left ventricular synchrony but has not been proven to be safe over the long term. We assessed the feasibility and safety of both HBP and LBBAP in AF pacing-dependent patients and compared the parameters of both leads at baseline and at the 6-month follow-up.

Methods: A total of 16 AF patients in our center, who successfully attempted both HBP and LBBAP, were prospectively enrolled unless only one of these treatment statuses was attained. The electrocardiogram characteristics, leading parameters, echocardiography results, and clinical outcomes were assessed.

Results: Thirteen out of 16 patients achieved both HBP and LBBAP successfully in the same AF pacing-dependent patients. In symptomatic HF patients with preserved left ventricular ejection fraction (LVEF) (n = 10), the left ventricular end-diastolic diameter (LVEDD) was reduced from 51.8 ± 4.4 to 48.3 ± 3.1 mm (p = 0.01) with the use of diuretics, either reduced or stopped (n = 7). During the follow-up, one patient in the group without HF had an increased HBP threshold and developed HF symptoms. His HF symptoms disappeared when switched into LBBAP mode. Another patient in the group with HF got his LVEF elevated by HBP for 3 months by utilizing left bundle branch block(LBBB)correction and continued to increase when switched into LBBAP for another 3 months due to an increased HBP correction threshold. The average unipolar pacing threshold of LBBAP was lower than that of HBP. No perforation or dislodgement occurred in our study.

Conclusion: Both HBP and LBBAP could be attempted successfully in the same AF patients when one of the two modes could be adopted and switched according to the clinical feasibility. Compared with HBP, LBBAP yielded better and more stable parameters but showed comparable effects during the 6-month follow-up.
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http://dx.doi.org/10.1007/s10840-021-00964-6DOI Listing
March 2021

Relationship between PD-L1 expression and outcome in EGFR-mutant lung cancer patients treated with EGFR tyrosine kinase inhibitors.

Lung Cancer 2021 May 9;155:28-33. Epub 2021 Mar 9.

Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. Electronic address:

Objectives: Predictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients.

Materials And Methods: Patients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression.

Results: A total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6-4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9-5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival.

Conclusion: In this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.004DOI Listing
May 2021

Divergent evolution profiles of DD37D and DD39D families of Tc1/mariner transposons in eukaryotes.

Mol Phylogenet Evol 2021 Mar 10;161:107143. Epub 2021 Mar 10.

College of Animal Science & Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China. Electronic address:

DNA transposons play a significant role in shaping the size and structure of eukaryotic genomes. The Tc1/mariner transposons are the most diverse and widely distributed superfamily of DNA transposons and the structure and distribution of several Tc1/mariner families, such as DD35E/TR, DD36E/IC, DD37E/TRT, and DD41D/VS, have been well studied. Nonetheless, a greater understanding of the structure and diversity of Tc1/mariner transposons will provide insight into the evolutionary history of eukaryotic genomes. Here, we conducted further analysis of DD37D/maT and DD39D (named Guest, GT), which were identified by the specific catalytic domains DD37D and DD39D. Most transposons of the maT family have a total length of approximately 1.3 kb and harbor a single open reading frame encoding a ~ 346 amino acid (range 302-398 aa) transposase protein, flanked by short terminal inverted repeats (TIRs) (13-48 base pairs, bp). In contrast, GTs transposons were longer (2.0-5.8 kb), encoded a transposase protein of ~400 aa (range 140-592 aa), and were flanked by short TIRs (19-41 bp). Several conserved motifs, including two helix-turn-helix (HTH) motifs, a GRPR (GRKR) motif, a nuclear localization sequence, and a DDD domain, were also identified in maT and GT transposases. Phylogenetic analyses of the DDD domain showed that the maT and GT families each belong to a monophyletic clade and appear to be closely related to DD41D/VS and DD34D/mariner. In addition, maTs are mainly distributed in invertebrates (144 species), whereas GTs are mainly distributed in land plants through a small number of GTs are present in Chromista and animals. Sequence identity and phylogenetic analysis revealed that horizontal transfer (HT) events of maT and GT might occur between kingdoms and phyla of eukaryotes; however, pairwise distance comparisons between host genes and transposons indicated that HT events involving maTs might be less frequent between invertebrate species and HT events involving GTs may be less frequent between land plant species. Overall, the DD37D/maT and DD39D/GT families display significantly different distribution and tend to be identified in more ancient evolutionary families. The discovery of intact transposases, perfect TIRs, and target site duplications (TSD) of maTs and GTs illustrates that the DD37D/maT and DD39D/GT families may be active. Together, these findings improve our understanding of the diversity of Tc1/mariner transposons and their impact on eukaryotic genome evolution.
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http://dx.doi.org/10.1016/j.ympev.2021.107143DOI Listing
March 2021

Identification of a New Potential Cd-Accumulator Pterocypsela indica (L.) Shih.

Bull Environ Contam Toxicol 2021 May 8;106(5):859-865. Epub 2021 Mar 8.

University of Chinese Academy of Sciences, Beijing, 100049, China.

Three experiments were conducted to investigate the Cd tolerance and accumulation ability of a forage grass, Pterocypsela indica. P. indica accumulated 31.40 and 69.68 mg/kg Cd in roots and shoots, respectively, and plant biomass was unaffected by soil Cd as high as 50 mg/kg. Cd pollution obviously increased the Cd content of the cell wall fraction and decreased that of the soluble fraction in plant roots, but had little effect on the subcellular Cd content in plant shoots. When soil was co-contaminated by 2.29 mg/kg Cd, 526.83 mg/kg Zn, and 595.38 mg/kg Pb, P. indica accumulated 61.63 mg/kg Cd, 4261.00 mg/kg Zn, and 75.27 mg/kg Pb in plant shoots. The results indicated that P. indica mainly detoxified Cd stress by improving the fixation of Cd on the cell wall of plant roots rather than shoots. P. indica is a potential Cd accumulator that has a high phytoremediation efficiency in Cd-Zn-contaminated soil.
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http://dx.doi.org/10.1007/s00128-021-03165-zDOI Listing
May 2021

First-Principles Study of Microscopic Electrochemistry at the LiCoO Cathode/LiNbO Coating/β-LiPS Solid Electrolyte Interfaces in an All-Solid-State Battery.

ACS Appl Mater Interfaces 2021 Mar 5;13(10):11765-11773. Epub 2021 Mar 5.

Center for Green Research on Energy and Environmental Materials (GREEN) and International Center for Materials Nanoarchitectonics (MANA), NIMS, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.

High interfacial resistance between electrode and solid electrolyte (SE) is one of the major challenges for the commercial application of all-solid-state batteries (ASSBs), and coating at the interface is an effective way for decreasing the resistance. However, microscopic electrochemistry especially for the electrochemical potential and the distribution of Li at the interface has not been well established yet, impeding the in-depth understanding of interfacial Li transport. Herein, we have introduced a potential energy profile for Li, η, and demonstrated that the interfacial η can be evaluated from the calculated interfacial Li vacancy formation energy or the bulk vacancy formation energy and the interface band alignment. Through computational analysis of the representative LiCoO cathode/LiNbO coating/β-LiPS SE interfaces using the novel interface structure prediction scheme based on the CALYPSO method, we found that η at the LiCoO/β-LiPS interface is highly disordered under the influence of the interface reconstruction and is rather electronic conductive. Insertion of LiNbO coating can effectively decrease the preference of ion mixing. Besides, the appropriate changes in band alignments lead to a decrease of difference in the interfacial η and lower resistances at the interfaces. The results provide a reliable explanation for the effectiveness of the coating layer observed experimentally. Furthermore, our study provides a guidance for the future simulation of the microscopic electrochemistry at the electrode/SE interfaces in ASSBs.
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http://dx.doi.org/10.1021/acsami.0c19091DOI Listing
March 2021

Overexpression of EZH2/NSD2 Histone Methyltransferase Axis Predicts Poor Prognosis and Accelerates Tumor Progression in Triple-Negative Breast Cancer.

Front Oncol 2020 16;10:600514. Epub 2021 Feb 16.

Department of Pathology, First Affiliated Hospital of Dali University, Dali, China.

Two histone methyltransferases, enhancer of zeste homolog 2 (EZH2) and nuclear SET domain-containing 2 (NSD2), are aberrantly expressed in several types of human cancers. However, the regulatory relationship between EZH2 and NSD2 and their prognostic values in breast cancer (BC) have not been fully elucidated. In this study, we demonstrated that EZH2 and NSD2 were overexpressed in BC compared with benign lesions and normal tissues using tissue microarray, immunohistochemistry, and bioinformatic databases. Both EZH2 and NSD2 expression were associated with pathological grade of tumor and lymph node metastasis. A comprehensive survival analysis using Kaplan-Meier Plotter database indicated that EZH2 expression was negatively correlated with relapse-free survival (RFS), overall survival (OS), distant metastasis-free survival (DMFS), and postprogression survival (PPS) in 3951 BC patients, and NSD2 expression was negatively correlated with RFS and DMFS. Notably, EZH2 and NSD2 expression were coordinately higher in triple-negative breast cancer (TNBC) than that in other subtypes. Stable knockdown of EZH2 using lentiviral shRNA vector significantly reduced the proliferation, migration and invasion abilities of TNBC cell line MDA-MB-231 and MDA-MB-468, and downregulated NSD2 expression as well as the levels of H3K27me3 and H3K36me2, two histone methylation markers catalyzed by EZH2 and NSD2, respectively. By contrast, overexpression of EZH2 using adenovirus vector displayed an inverse phenotype. Furthermore, knockdown of NSD2 in EZH2-overexpressing cells could dramatically attenuate EZH2-mediated oncogenic effects. Bioinformatic analysis further revealed the function and pathway enrichments of co-expressed genes and interactive genes of EZH2/NSD2 axis, suggesting that EZH2/NSD2 axis was associated with cell division, mitotic nuclear division and transition of mitotic cell cycle in TNBC. Taken together, EZH2/NSD2 axis may act as a predictive marker for poor prognosis and accelerate the progression of TNBC.
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http://dx.doi.org/10.3389/fonc.2020.600514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921704PMC
February 2021

A native, highly active Tc1/mariner transposon from zebrafish (ZB) offers an efficient genetic manipulation tool for vertebrates.

Nucleic Acids Res 2021 02;49(4):2126-2140

College of Animal Science & Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.

New genetic tools and strategies are currently under development to facilitate functional genomics analyses. Here, we describe an active member of the Tc1/mariner transposon superfamily, named ZB, which invaded the zebrafish genome very recently. ZB exhibits high activity in vertebrate cells, in the range of those of the widely used transposons piggyBac (PB), Sleeping Beauty (SB) and Tol2. ZB has a similar structural organization and target site sequence preference to SB, but a different integration profile with respect to genome-wide preference among mammalian functional annotation features. Namely, ZB displays a preference for integration into transcriptional regulatory regions of genes. Accordingly, we demonstrate the utility of ZB for enhancer trapping in zebrafish embryos and in the mouse germline. These results indicate that ZB may be a powerful tool for genetic manipulation in vertebrate model species.
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http://dx.doi.org/10.1093/nar/gkab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913693PMC
February 2021

Inhibition of anti-viral stress granule formation by coronavirus endoribonuclease nsp15 ensures efficient virus replication.

PLoS Pathog 2021 02 26;17(2):e1008690. Epub 2021 Feb 26.

Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. China.

Cytoplasmic stress granules (SGs) are generally triggered by stress-induced translation arrest for storing mRNAs. Recently, it has been shown that SGs exert anti-viral functions due to their involvement in protein synthesis shut off and recruitment of innate immune signaling intermediates. The largest RNA viruses, coronaviruses, impose great threat to public safety and animal health; however, the significance of SGs in coronavirus infection is largely unknown. Infectious Bronchitis Virus (IBV) is the first identified coronavirus in 1930s and has been prevalent in poultry farm for many years. In this study, we provided evidence that IBV overcomes the host antiviral response by inhibiting SGs formation via the virus-encoded endoribonuclease nsp15. By immunofluorescence analysis, we observed that IBV infection not only did not trigger SGs formation in approximately 80% of the infected cells, but also impaired the formation of SGs triggered by heat shock, sodium arsenite, or NaCl stimuli. We further demonstrated that the intrinsic endoribonuclease activity of nsp15 was responsible for the interference of SGs formation. In fact, nsp15-defective recombinant IBV (rIBV-nsp15-H238A) greatly induced the formation of SGs, along with accumulation of dsRNA and activation of PKR, whereas wild type IBV failed to do so. Consequently, infection with rIBV-nsp15-H238A strongly triggered transcription of IFN-β which in turn greatly affected rIBV-nsp15-H238A replication. Further analysis showed that SGs function as an antiviral hub, as demonstrated by the attenuated IRF3-IFN response and increased production of IBV in SG-defective cells. Additional evidence includes the aggregation of pattern recognition receptors (PRRs) and signaling intermediates to the IBV-induced SGs. Collectively, our data demonstrate that the endoribonuclease nsp15 of IBV interferes with the formation of antiviral hub SGs by regulating the accumulation of viral dsRNA and by antagonizing the activation of PKR, eventually ensuring productive virus replication. We further demonstrated that nsp15s from PEDV, TGEV, SARS-CoV, and SARS-CoV-2 harbor the conserved function to interfere with the formation of chemically-induced SGs. Thus, we speculate that coronaviruses employ similar nsp15-mediated mechanisms to antagonize the host anti-viral SGs formation to ensure efficient virus replication.
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http://dx.doi.org/10.1371/journal.ppat.1008690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946191PMC
February 2021

Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p.

Stem Cell Res Ther 2021 Feb 25;12(1):150. Epub 2021 Feb 25.

Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, #107 West Yan Jiang Road, Guangzhou, Guangdong, 510120, China.

Background: Little is known about the implications of circRNAs in the effects of melatonin (MEL) on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoporosis (OP) progression. The aim of our study was to investigate circRNAs in MEL-regulated BMSC differentiation and OP progression.

Methods: BMSC osteogenic differentiation was measured by qRT-PCR, western blot (WB), Alizarin Red, and alkaline phosphatase (ALP) staining. Differential circRNA and mRNA profiles of BMSCs treated by MEL were characterized by deep sequencing, followed by validation using RT-PCR, Sanger sequencing, and qRT-PCR. Silencing and overexpression of circ_0003865 were conducted for functional investigations. The sponged microRNAs and targeted mRNAs were predicted by bioinformatics and validated by qRT-PCR, RNA pull-down, and dual-luciferase reporter assay. The function of miR-3653-3p and circ_0003865/miR-3653-3p/growth arrest-specific gene 1 (GAS1) cascade was validated for the osteogenic differentiation of BMSCs by CCK-8, qRT-PCR, WB, Alizarin Red, and ALP staining. The effects of circ_0003865 on OP development were tested in murine OP model.

Results: MEL promoted osteogenic differentiation of BMSCs. RNA sequencing revealed significant alterations in circRNA and mRNA profiles associated with multiple biological processes and signaling pathways. Circ_0003865 expression in BMSCs was significantly decreased by MEL treatment. Silencing of circ_0003865 had no effect on proliferation while promoted osteogenic differentiation of BMSCs. Overexpression of circ_0003865 abrogated the promotion of BMSC osteogenic differentiation induced by MEL, but proliferation of BMSCs induced by MEL had no change whether circ_0003865 was overexpression or not. Furthermore, circ_0003865 sponged miR-3653-3p to promote GAS1 expression in BMSCs. BMSC osteogenic differentiation was enhanced by miR-3653-3p overexpression while BMSC proliferation was not affected. By contrast, miR-3653-3p silencing mitigated the promoted BMSC osteogenic differentiation caused by circ_0003865 silencing, but had no effect on proliferation. Finally, circ_0003865 silencing repressed OP development in mouse model.

Conclusion: MEL promotes BMSC osteogenic differentiation and inhibits OP pathogenesis by suppressing the expression of circ_0003865, which regulates GAS1 gene expression via sponging miR-3653-3p.
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http://dx.doi.org/10.1186/s13287-021-02224-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908669PMC
February 2021

Transcription activation by a sliding clamp.

Nat Commun 2021 02 18;12(1):1131. Epub 2021 Feb 18.

Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Transcription activation of bacteriophage T4 late genes is accomplished by a transcription activation complex containing RNA polymerase (RNAP), the promoter specificity factor gp55, the coactivator gp33, and a universal component of cellular DNA replication, the sliding clamp gp45. Although genetic and biochemical studies have elucidated many aspects of T4 late gene transcription, no precise structure of the transcription machinery in the process is available. Here, we report the cryo-EM structures of a gp55-dependent RNAP-promoter open complex and an intact gp45-dependent transcription activation complex. The structures reveal the interactions between gp55 and the promoter DNA that mediate the recognition of T4 late promoters. In addition to the σR2 homology domain, gp55 has a helix-loop-helix motif that chaperons the template-strand single-stranded DNA of the transcription bubble. Gp33 contacts both RNAP and the upstream double-stranded DNA. Gp45 encircles the DNA and tethers RNAP to it, supporting the idea that gp45 switches the promoter search from three-dimensional diffusion mode to one-dimensional scanning mode.
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http://dx.doi.org/10.1038/s41467-021-21392-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892883PMC
February 2021

Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial.

Lancet 2021 Feb;397(10274):592-604

Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.

Background: We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%.

Methods: In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing.

Findings: Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy.

Interpretation: Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population.

Funding: Regeneron Pharmaceuticals and Sanofi.
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http://dx.doi.org/10.1016/S0140-6736(21)00228-2DOI Listing
February 2021

Cerebrovascular disease in pregnancy and puerperium: perspectives from neuroradiologists.

Quant Imaging Med Surg 2021 Feb;11(2):838-851

Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Pregnancy-related cerebrovascular disease is a serious complication of pregnancy and puerperium. The etiology and pathological mechanisms of cerebrovascular disease are complex, involving changes in the cardiovascular, endocrine, and immune systems. Vascular risk factors during pregnancy and puerperium may cause vasospasm and endothelial cell damage leading to cerebral ischemia, hemorrhage, posterior reversible encephalopathy syndrome (PRES), and reversible cerebral vasoconstriction syndrome. Arterial or venous obstruction may damage the blood-brain barrier (BBB) and impede venous return, resulting in cerebral edema, hemorrhage, and intracranial hypertension. Pregnancy with hypercoagulability may threaten the lives of both the mother and the developing fetus. With improvements in stroke treatment during pregnancy and puerperium, neuroradiologists have gained new insights into this problem. This article reviews the pathogenesis, imaging findings, and risk factors of stroke during pregnancy and puerperium, focusing on imaging diagnosis and prognostic assessment.
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http://dx.doi.org/10.21037/qims-20-830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779914PMC
February 2021

Profiling gene expression reveals insights into pulmonary response to aerosolized botulinum toxin type A exposure in mice.

J Appl Toxicol 2021 Feb 2. Epub 2021 Feb 2.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.

Botulinum neurotoxin type A (BoNT/A) is traditional medicine and well known for its therapeutic use as an anesthetic and in cosmetic applications that work through the inhibition of acetylcholine exocytosis in neuronal cells. BoNT/A also has the potential to function as a biological weapon due to its high mortality rate and ease of dispersal. Emerging evidence suggests that BoNT/A exhibits biological effects on nonneuronal cells. In cytology experiments, BoNT/A induces global gene expression alterations. However, pulmonary effects from exposure to aerosolized BoNT/A have not been evaluated. This study investigated the global transcriptional profile of lung tissues after botulism inhalation. A mice model of inhaled botulism was established using intratracheal exposure to aerosolized BoNT/A and described through histological examination and flow cytometry. Transcriptomic analysis revealed that genes related to acute inflammatory responses were upregulated at 12-h postexposure. Increased expression of multiple anti-inflammatory marker genes and decreased expression of pro-inflammatory marker genes were observed at 48- to 72-h postexposure, underscoring a transcriptional shift toward a pro-reparative phenotype. Histological examination and cell proportions analysis mirrored these expression patterns. Accordingly, the orchestration of a quick phenotype transition prompted by BoNT/A may have the potential for promoting the resolution of the inflammatory lung. To our knowledge, this study represents the first research to investigate the pulmonary transcriptional responses of aerosolized BoNT/A exposure; the results may provide new insights in elucidating the molecular mechanism for pulmonary inhaled botulism and highlight the potential therapeutic application of BoNT/A in mitigating inflammatory conditions.
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http://dx.doi.org/10.1002/jat.4140DOI Listing
February 2021

GutBalance: a server for the human gut microbiome-based disease prediction and biomarker discovery with compositionality addressed.

Brief Bioinform 2021 Jan 30. Epub 2021 Jan 30.

Department of Radiology, The Second Affiliated Hospital, Harbin Medical University, Harbin 150001, China.

The compositionality of the microbiome data is well-known but often neglected. The compositional transformation pertains to the supervised learning of microbiome data and is a critical step that decides the performance and reliability of the disease classifiers. We value the excellent performance of the distal discriminative balance analysis (DBA) method, which selects distal balances of pairs and trios of bacteria, in addressing the classification of high-dimensional microbiome data. By applying this method to the species-level abundances of all the disease phenotypes in the GMrepo database, we build a balance-based model repository for the classification of human gut microbiome-related diseases. The model repository supports the prediction of disease risks for new sample(s). More importantly, we highlight the concept of balance-disease associations rather than the conventional microbe-disease associations and develop the human Gut Balance-Disease Association Database (GBDAD). Each predictable balance for each disease model indicates a potential biomarker-disease relationship and can be interpreted as a bacteria ratio positively or negatively correlated with the disease. Furthermore, by linking the balance-disease associations to the evidenced microbe-disease associations in MicroPhenoDB, we surprisingly found that most species-disease associations inferred from the shotgun metagenomic datasets can be validated by external evidence beyond MicroPhenoDB. The balance-based species-disease association inference will accelerate the generation of new microbe-disease association hypotheses in gastrointestinal microecology research and clinical trials. The model repository and the GBDAD database are deployed on the GutBalance server, which supports interactive visualization and systematic interrogation of the disease models, disease-related balances and disease-related species of interest.
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http://dx.doi.org/10.1093/bib/bbaa436DOI Listing
January 2021

Multiphoton microfabrication and micropatterning (MMM) - An all-in-one platform for engineering biomimetic soluble cell niches.

Biomaterials 2021 Feb 5;269:120644. Epub 2021 Jan 5.

Tissue Engineering Laboratory, Department of Mechanical Engineering, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region, China. Electronic address:

Engineered biomimetic cell niches represent a valuable in vitro tool for investigating physiological and pathological cellular activities, while developing an all-in-one technology to engineer cell niches, particularly soluble cell niche factors, with retained bioactivities, remains challenging. Here, we report a mask-free, non-contact and biocompatible multiphoton microfabrication and micropatterning (MMM) technology in engineering a spatially and quantitatively controllable bone morphogenetic protein-2 (BMP-2) soluble niche, by immobilizing optimally biotinylated BMP-2 (bBMP-2) on micro-printed neutravidin (NA) micropatterns. Notably, the micropatterned NA bound-bBMP-2 niche elicited a more sustained and a higher level of the downstream Smad signaling than that by free BMP-2, in C2C12 cells, suggesting the advantages of immobilizing soluble niche factors on engineered micropatterns or scaffold materials. This work reports a universal all-in-one cell niche engineering platform and contributes to reconstituting heterogeneous native soluble cell niches for signal transduction modeling and drug screening studies.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120644DOI Listing
February 2021

Extraction, Radical Scavenging Activities, and Chemical Composition Identification of Flavonoids from Sunflower ( L.) Receptacles.

Molecules 2021 Jan 14;26(2). Epub 2021 Jan 14.

School of Life Sciences, Jilin University, Changchun 130012, China.

This study was focused on extraction, radical scavenging activities, and chemical composition identification of total flavonoids in sunflower ( L.) receptacles (TFSR). We investigated the optimal extract parameters of TFSR using response surface methodology. The highest yield of TFSR was 1.04% with the ethanol concentration 58%, the material-to-liquid ratio 1:20 (/), the extraction time 2.6 h, and the extraction temperature 67 °C. The results of radical scavenging activities showed that ethyl acetate fraction (EAF) was the strongest by using 2-diphenyl-1-picrylhydrazyl (DPPH), 2, 2'-azino-bis (3-ethylbenzo thiazoline-6-sulfonic acid) (ABTS) and iron ion reducing analysis. The EAF had the highest flavonoids contents. Four fractions A, B, C and D were enrichment from EAF by polyamide resin. Fraction B had the highest flavonoids content. Thirteen chemical components of flavonoids in fraction B were first identified by Ultimate 3000 Nano LC System coupled to a Q Exactive HF benchtop Orbitrap mass spectrometer (UHPLC-HRMS/MS). Among of the thirteen chemical components, isoquercetin and daidzein were identified accurately by comparing with standard samples. Radical scavenging analysis showed that isoquercetin and EAF had strong activities. Therefore, sunflower receptacles can be used as a source of natural flavonoids. TFSR as a natural radical scavenger has potential applications in pharmaceutical industry.
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http://dx.doi.org/10.3390/molecules26020403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828773PMC
January 2021