Publications by authors named "Xiaolong Fu"

76 Publications

Lindl. alkaloids alleviate Mn-induced neurotoxicity via PINK1/Parkin-mediated mitophagy in PC12 cells.

Biochem Biophys Rep 2021 Jul 2;26:100877. Epub 2021 Apr 2.

Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.

Modern pharmacological studies have demonstrated that Lindl. Alkaloids (DNLA), the main active ingredients of , is valuable as an anti-aging and neuroprotective herbal medicine. The present study was designed to determine whether DNLA confers protective function over neurotoxicant manganese (Mn)-induced cytotoxicity and the mechanism involved. Our results showed that pretreatment of PC12 cells with DNLA alleviated cell toxicity induced by Mn and improved mitochondrial respiratory capacity and oxidative status. Mn treatment increased apoptotic cell death along with a marked increase in the protein expression of Bax and a decrease in the expression of Bcl-2 protein, all of which were noticeably reversed by DNLA. Furthermore, DNLA significantly abolished the decrease in protein levels of both PINK1 and Parkin, and mitigated the increased expression of autophagy marker LC3-II and accumulation of p62 caused by Mn. These results demonstrate that DNLA inhibits Mn induced cytotoxicity, which may be mediated through modulating PINK1/Parkin-mediated autophagic flux and improving mitochondrial function.
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http://dx.doi.org/10.1016/j.bbrep.2020.100877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047462PMC
July 2021

Piccolo is essential for the maintenance of mouse retina but not cochlear hair cell function.

Aging (Albany NY) 2021 Apr 21;13(8):11678-11695. Epub 2021 Apr 21.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan 250100, China.

Piccolo is a presynaptic protein with high conservation among different species, and the expression of Piccolo is extensive in vertebrates. Recently, a small fragment of Piccolo (Piccolino), arising due to the incomplete splicing of intron 5/6, was found to be present in the synapses of retinas and cochleae. However, the comprehensive function of Piccolo in the retina and cochlea remains unclear. In this study, we generated knockout mice using CRISPR-Cas9 technology to explore the function of Piccolo. Unexpectedly, whereas no abnormalities were found in the cochlear hair cells of the mutant mice, significant differences were found in the retinas, in which two layers (the outer nuclear layer and the outer plexiform layer) were absent. Additionally, the amplitudes of electroretinograms were significantly reduced and pigmentation was observed in the fundoscopy of the mutant mouse retinas. The expression levels of Bassoon, a homolog of Piccolo, as well as synapse-associated proteins CtBP1, CtBP2, Kif3A, and Rim1 were down-regulated. The numbers of ribbon synapses in the retinas of the mutant mice were also reduced. Altogether, the phenotype of -/- mice resembled the symptoms of retinitis pigmentosa (RP) in humans, suggesting might be a candidate gene of RP and indicates knockout mice are a good model for elucidating the molecular mechanisms of RP.
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http://dx.doi.org/10.18632/aging.202861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109093PMC
April 2021

Deletion of in Mice Does Not Alter Auditory Function.

Front Cell Dev Biol 2021 22;9:630361. Epub 2021 Feb 22.

Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Endolymphatic potential (EP) is the main driving force behind the sensory transduction of hearing, and K is the main charge carrier. Kir5.1 is a K transporter that plays a significant role in maintaining EP homeostasis, but the expression pattern and role of Kir5.1 (which is encoded by the gene) in the mouse auditory system has remained unclear. In this study, we found that Kir5.1 was expressed in the mouse cochlea. We checked the inner ear morphology and measured auditory function in mice and found that loss of did not appear to affect the development of hair cells. There was no significant difference in auditory function between mice and wild-type littermates, although the expression of , , and were significantly decreased in the mice. Additionally, no significant differences were found in the number or distribution of ribbon synapses between the and wild-type mice. In summary, our results suggest that the gene is not essential for auditory function in mice.
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http://dx.doi.org/10.3389/fcell.2021.630361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937937PMC
February 2021

KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma.

Future Oncol 2021 Apr 3;17(10):1143-1153. Epub 2021 Feb 3.

Department of Medical Oncology, Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA 02215-5450, USA.

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. NCT04210115 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927908PMC
April 2021

Deep learning-based automatic delineation of the hippocampus by MRI: geometric and dosimetric evaluation.

Radiat Oncol 2021 Jan 14;16(1):12. Epub 2021 Jan 14.

Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China.

Background: Whole brain radiotherapy (WBRT) can impair patients' cognitive function. Hippocampal avoidance during WBRT can potentially prevent this side effect. However, manually delineating the target area is time-consuming and difficult. Here, we proposed a credible approach of automatic hippocampal delineation based on convolutional neural networks.

Methods: Referring to the hippocampus contouring atlas proposed by RTOG 0933, we manually delineated (MD) the hippocampus on the MRI data sets (3-dimensional T1-weighted with slice thickness of 1 mm, n = 175), which were used to construct a three-dimensional convolutional neural network aiming for the hippocampus automatic delineation (AD). The performance of this AD tool was tested on three cohorts: (a) 3D T1 MRI with 1-mm slice thickness (n = 30); (b) non-3D T1-weighted MRI with 3-mm slice thickness (n = 19); (c) non-3D T1-weighted MRI with 1-mm slice thickness (n = 11). All MRIs confirmed with normal hippocampus has not been violated by any disease. Virtual radiation plans were created for AD and MD hippocampi in cohort c to evaluate the clinical feasibility of the artificial intelligence approach. Statistical analyses were performed using SPSS version 23. P < 0.05 was considered significant.

Results: The Dice similarity coefficient (DSC) and Average Hausdorff Distance (AVD) between the AD and MD hippocampi are 0.86 ± 0.028 and 0.18 ± 0.050 cm in cohort a, 0.76 ± 0.035 and 0.31 ± 0.064 cm in cohort b, 0.80 ± 0.015 and 0.24 ± 0.021 cm in cohort c, respectively. The DSC and AVD in cohort a were better than those in cohorts b and c (P < 0.01). There is no significant difference between the radiotherapy plans generated using the AD and MD hippocampi.

Conclusion: The AD of the hippocampus based on a deep learning algorithm showed satisfying results, which could have a positive impact on improving delineation accuracy and reducing work load.
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http://dx.doi.org/10.1186/s13014-020-01724-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807715PMC
January 2021

Ce-Based Nanoparticles Loaded with Cisplatin for Tumour Radiotherapy.

J Biomed Nanotechnol 2020 Oct;16(10):1482-1494

The combination of radiotherapy and chemotherapy is a common and useful treatment mode for tumours. But traditional methods inevitably lead to a variety of side effects. A drug delivery system (DDS), which has good biocompatibility and strong anti-tumour ability, is expected to solve this problem. Studies have shown that Ce-based nanoparticles (NPs) have good radiosensitization effect through the photoelectric effect. Hence, cisplatin-loaded LiLuF₄ :Cescintillation NPs (NP + Cis) were first constructed in this study, which was synthesized by the crystal precipitation method and characterized by transmission electron microscopy (TEM). Subsequently, its toxicity was verified, and the radiosensitization effect and basic radiosensitization mechanism on tumour cells and tumour-bearing mice were researched. Results showed that NP + Cis triggered massive DNA damage and effectively inhibited cell viability in vitro under the exposure of X-ray irradiation (IR). Moreover, the experiments in vivo showed that the NP + Cis had higher biosafety, which could absorb enough irradiation and produce a synergistic inhibitory effect on tumours through the releasing of Cis. NP + Cis can improve the performance of DDS in chemoradiotherapy.
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http://dx.doi.org/10.1166/jbn.2020.2984DOI Listing
October 2020

Multiple Single-Nucleotide Polymorphism Detection for Antimalarial Pyrimethamine Resistance via Allele-Specific PCR Coupled with Gold Nanoparticle-Based Lateral Flow Biosensor.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Department of Human Parasitology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China

Molecular genotyping holds tremendous potential to detect antimalarial drug resistance (ADR) related to single nucleotide polymorphisms (SNPs). However, it relies on the use of complicated procedures and expensive instruments. Thus, rapid point-of-care testing (POCT) molecular tools are urgently needed for field survey and clinical use. Herein, a POCT platform consisting of multiple-allele-specific PCR (AS-PCR) and a gold nanoparticle (AuNP)-based lateral flow biosensor was designed and developed for SNP detection of the dihydrofolate reductase () gene related to pyrimethamine resistance. The multiple-AS-PCR utilized 3' terminal artificial antepenultimate mismatch and double phosphorothioate-modified allele-specific primers. The duplex PCR amplicons with 5' terminal labeled with biotin and digoxin are recognized by streptavidin (SA)-AuNPs on the conjugate pad and then captured by anti-digoxin antibody through immunoreactions on the test line to produce a golden red line for detection. The system was applied to analyze SNPs in Pfdhfr N51I, C59R, and S108N of 98 clinical isolates from uncomplicated malaria patients. Compared with the results from nested PCR followed by Sanger DNA sequencing, the sensitivity was 97.96% (96/98) for N51I, C59R, and S108N. For specificity, the values were 100% (98/98), 95.92% (94/98), and 100% (98/98) for N51I, C59R, and S108N, respectively. The limit of detection is approximately 200 fg/μl for plasmid DNA as the template and 100 parasites/μl for blood filter paper. The established platform not only offers a powerful tool for molecular surveillance of ADR but also is easily extended to interrelated SNP profiles for infectious diseases and genetic diseases.
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http://dx.doi.org/10.1128/AAC.01063-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092547PMC
February 2021

Erlotinib Versus Etoposide/Cisplatin With Radiation Therapy in Unresectable Stage III Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter, Randomized, Open-Label, Phase 2 Trial.

Int J Radiat Oncol Biol Phys 2021 Apr 19;109(5):1349-1358. Epub 2020 Nov 19.

Department of Radiation Oncology and Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China. Electronic address:

Purpose: This study aimed to compare erlotinib (E) and etoposide/cisplatin (EP) with concurrent radiation therapy (RT) for patients with stage IIIA/B unresectable advanced non-small cell lung cancer with activating epidermal growth factor receptor mutation (EGFRm+).

Methods And Patients: This was a multicenter, randomized, open-label, phase 2 trial conducted across 19 institutions in China (December 2012 to January 2016). Enrolled patients were randomized (1:1) to E + RT (oral erlotinib 150 mg/d for 2 years or until disease progression or intolerable toxicity and RT 200 cGy/d, 5 d/wk for 6 weeks from the first day of erlotinib) or EP + RT (etoposide 50 mg/m intravenously on days 1-5 and 29-33; cisplatin 50 mg/m intravenously on days 1, 8, 29 and 36; and RT as for E + RT). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate and safety.

Results: Two hundred fifty-two patients were screened, and 20 patients with EGFRm+ in each group received the allocated E + RT or EP + RT treatment. Patient characteristics were well balanced between groups. Compared with EP + RT, median PFS with E + RT was significantly longer (24.5 vs 9.0 months [hazard ratio, 0.104; 95% confidence interval, 0.028-0.389; P < .001]). Objective response rate in the E + RT and EP + RT groups was 70% and 61.9%, respectively (P = .744). The incidence of adverse events (any grade) was similar between E + RT and EP + RT groups (88.9% and 84.2%).

Conclusions: The primary endpoint of PFS was met, and the data showed that E + RT might provide PFS improvement compared with EP + RT, with similar tolerability. However, definitive statements regarding the efficacy of concurrent E + RT in patients with unresectable stage III non-small cell lung cancer with activating EGFRm+ cannot be made, and slow patient accrual will likely make it infeasible to conduct a phase 3 study.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.026DOI Listing
April 2021

Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage.

Front Cell Dev Biol 2020 31;8:712. Epub 2020 Aug 31.

Jiangsu Provincial Key Medical Discipline (Laboratory), Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.

Aminoglycoside-induced hair cell (HC) loss is one of the most important causes of hearing loss. After entering the inner ear, aminoglycosides induce the production of high levels of reactive oxygen species (ROS) that subsequently activate apoptosis in HCs. Citicoline, a nucleoside derivative, plays a therapeutic role in central nervous system injury and in neurodegenerative disease models, including addictive disorders, stroke, head trauma, and cognitive impairment in the elderly, and has been widely used in the clinic as an FDA approved drug. However, its effect on auditory HCs remains unknown. Here, we used HC-like HEI-OC-1 cells and whole organ explant cultured mouse cochleae to explore the effect of citicoline on aminoglycoside-induced HC damage. Consistent with previous reports, both ROS levels and apoptosis were significantly increased in neomycin-induced cochlear HCs and HEI-OC-1 cells compared to undamaged controls. Interestingly, we found that co-treatment with citicoline significantly protected against neomycin-induced HC loss in both HEI-OC-1 cells and whole organ explant cultured cochleae. Furthermore, we demonstrated that citicoline could significantly reduce neomycin-induced mitochondrial dysfunction and inhibit neomycin-induced ROS accumulation and subsequent apoptosis. Thus, we conclude that citicoline can protect against neomycin-induced HC loss by inhibiting ROS aggregation and thus preventing apoptosis in HCs, and this suggests that citicoline might serve as a potential therapeutic drug in the clinic to protect HCs.
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http://dx.doi.org/10.3389/fcell.2020.00712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487320PMC
August 2020

A Novel Anticancer Therapeutic Strategy to Target Autophagy Accelerates Radiation-Associated Atherosclerosis.

Int J Radiat Oncol Biol Phys 2021 Feb 15;109(2):540-552. Epub 2020 Sep 15.

Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Purpose: Autophagy inhibition is a novel therapeutic strategy suggested for patients with advanced cancer, especially those who have undergone radiation therapy. In the present study, we investigated whether autophagy inhibitors accelerate the progression of radiation-associated atherosclerosis (RAA).

Methods And Materials: Eight-week-old apolipoprotein (ApoE) mice were fed a Western diet, and their left common carotid arteries were partially ligated to induce atherogenesis. Four weeks later, local ionizing radiation (IR) at a dose of 5 or 10 Gy was used to induce RAA in the left common carotid artery. After another 4 weeks, severe plaque burden associated with increased macrophage infiltration and lipid deposition, reduced smooth muscle cells, and decreased collagen expression was observed. In addition, these changes occurred in a dose-dependent manner. Improved autophagic flux caused by IR was observed in both macrophages of the atherosclerotic plaque and peritoneal macrophages in vitro. The inhibition of autophagic flux by chloroquine (50 mg/kg/d) further accelerated the progression of RAA in the left common carotid arteries of ApoE mice. Furthermore, chloroquine treatment exacerbated IR-induced p65 nuclear translocation, IκBα degradation, and transcription of nuclear factor-κB (NF-κB) target genes in peritoneal macrophages.

Conclusions: IR promotes atherogenesis and increases autophagic flux. In addition, autophagy inhibition by chloroquine accelerates the progression of RAA lesions by stimulating NF-κB-mediated inflammatory responses in macrophages.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.007DOI Listing
February 2021

On the optimal number of dose-limiting shells in the SBRT auto-planning design for peripheral lung cancer.

J Appl Clin Med Phys 2020 Sep 23;21(9):134-142. Epub 2020 Jul 23.

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.

Purpose: The number of dose-limiting shells in the optimization process is one of the key factors determining the quality of stereotactic body radiotherapy (SBRT) auto-planning in the Pinnacle treatment planning system (TPS). This study attempted to derive the optimal number of shells by evaluating the auto-plans designed with different number of shells for peripheral lung cancer patients treated with SBRT.

Methods: Identical treatment technique, optimization process, constraints, and dose calculation algorithm in the Pinnacle TPS were retrospectively applied to 50 peripheral lung cancer patients who underwent SBRT in our center. For each of the patients, auto-plans were optimized based on two shells, three shells, four shells, five shells, six shells, seven shells, eight shells, respectively. The optimal number of shells for the SBRT auto-planning was derived through the evaluations and comparisons of various dosimetric parameters of planning target volume (PTV) and organs at risk (OARs), monitor units (MU), and optimization time of the plans.

Results: The conformity index (CI) and the gradient index (GI) of PTV, the maximum dose outside the 2 cm of PTV (D ), D of spinal cord (SC ), the percentage of volume of total lung excluding ITV receiving 20 Gy (V20) and 10 Gy (V10), and the mean lung dose (MLD) were improved when the number of shell increased, but the improvement became not significant as the number of shell reached six. The monitor units (MUs) varied little among different plans where no statistical differences were found. However, as the number of shell increased, the auto-plan optimization time increased significantly.

Conclusions: It appears that for peripheral lung SBRT plan using six shells can yield satisfactory plan quality with acceptable beam MUs and optimization time in the Pinnacle TPS.
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http://dx.doi.org/10.1002/acm2.12983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497906PMC
September 2020

GATA6 Exerts Potent Lung Cancer Suppressive Function by Inducing Cell Senescence.

Front Oncol 2020 12;10:824. Epub 2020 Jun 12.

Key Laboratory of Functional Protein Research of Guangdong Higher Education, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.

Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here, we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth and tumorigenesis . Mechanistically, GATA6 upregulated p53 and p21 mRNA while it inhibited AKT activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic slowdown of growth rate of established lung tumor xenograft .
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http://dx.doi.org/10.3389/fonc.2020.00824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304445PMC
June 2020

One-Pot Domino Carbonylation Protocol for Aromatic Diimides toward n-Type Organic Semiconductors.

Angew Chem Int Ed Engl 2020 Aug 8;59(33):14024-14028. Epub 2020 Jun 8.

Key Laboratory of Organic Solids, Bejing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing, 100190, China.

Aromatic diimides are one of the most important chromophores in the construction of n-type organic semiconductors, which lag far behind their p-type counterpart but are necessary for ambipolar transistors, p-n junctions and organic complementary circuits. Herein, we establish a facile one-pot domino synthetic protocol for aromatic diimides via palladium-catalyzed carbonylation of tetrabromo aromatic precursors. Taking tetrabromocorannulene (TBrCor) and tetrabromo-2,7-di-tert-butylpyrene (TBrPy) as the typical examples, we obtained diimide derivatives in yields of about 50 %, one order of magnitude higher than that of the traditional multi-step diimidization. As demonstrated in the case of corannulene diimide, the efficient diimidization not only allows the LUMO levels to be lowered significantly but also provides an ordered and closer packing structures, opening up possibilities to the development of n-type semiconducting materials based on a variety of aromatic systems.
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http://dx.doi.org/10.1002/anie.202003179DOI Listing
August 2020

Clinical significance of age at diagnosis among patients with thymic epithelial tumors: a population-based study.

Aging (Albany NY) 2020 03 30;12(6):4815-4821. Epub 2020 Mar 30.

Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

Background: To investigate the clinicopathologic characteristics and survival outcomes of patients with thymic epithelial tumors (TET) according to age at diagnosis.

Results: A total of 4431 patients were analyzed. Gender, race, tumor histology and surgery were similar between different age groups. The 0-18 group was associated with a higher risk of distant metastasis. Compared to patients aged above 80, the hazard ratios (HR) for patients aged 0-18, 19-30, 31-40, 41-50, 51-60, 61-70, 71-80 were 1.079, 0.739, 0.614, 0.621, 0.633, 0.673, 0.861, respectively. From the subgroup analysis for the adult patients who were above 19 years old, we found that the 19-70 group had significant better cancer specific survival (CSS) and overall survival (OS) than the above 70 group.

Conclusions: Age is a strong independent prognostic factor for survival in TET. Pediatric TET has a higher risk of distant metastasis and an inferior CSS. For the adults who were above 19, patients older than 70-year-old were associated with a shorter CSS.

Methods: Information of 4431 TET patients was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Demographic features, clinicopathologic characteristics and survival outcomes were compared between patients diagnosed at different age groups (0-18, 19-30, 31-40, 41-50, 51-60, 61-70, 71-80, above 80).
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http://dx.doi.org/10.18632/aging.102897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138550PMC
March 2020

Predictive model of the first failure pattern in patients receiving definitive chemoradiotherapy for inoperable locally advanced non-small cell lung cancer (LA-NSCLC).

Radiat Oncol 2020 Feb 18;15(1):43. Epub 2020 Feb 18.

Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.

Purpose: To analyze patterns of failure in patients with LA-NSCLC who received definitive chemoradiotherapy (CRT) and to build a nomogram for predicting the failure patterns in this population of patients.

Materials And Methods: Clinicopathological data of patients with LA-NSCLC who received definitive chemoradiotherapy and follow-up between 2013 and 2016 in our hospital were collected. The endpoint was the first failure after definitive chemoradiotherapy. With using elastic net regression and 5-fold nested cross-validation, the optimal model with better generalization ability was selected. Based on the selected model and corresponding features, a nomogram prediction model was built. This model was also validated by ROC curves, calibration curve and decision curve analysis (DCA).

Results: With a median follow-up of 28 months, 100 patients experienced failure. There were 46 and 54 patients who experience local failure and distant failure, respectively. Predictive model including 9 factors (smoking, pathology, location, EGFR mutation, age, tumor diameter, clinical N stage, consolidation chemotherapy and radiation dose) was finally built with the best performance. The average area under the ROC curve (AUC) with 5-fold nested cross-validation was 0.719, which was better than any factors alone. The calibration curve revealed a satisfactory consistency between the predicted distant failure rates and the actual observations. DCA showed most of the threshold probabilities in this model were with good net benefits.

Conclusion: Clinicopathological factors could collaboratively predict failure patterns in patients with LA-NSCLC who are receiving definitive chemoradiotherapy. A nomogram was built and validated based on these factors, showing a potential predictive value in clinical practice.
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http://dx.doi.org/10.1186/s13014-020-1467-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029470PMC
February 2020

The Effects of Metal Complexes of Nano-Graphene Oxide to Thermal Decomposition of FOX-7.

Nanomaterials (Basel) 2020 Jan 13;10(1). Epub 2020 Jan 13.

Key Laboratory of Applied Surface and Colloid Chemistry, MOE/School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an 710062, China.

1,1-diamino-2,2-dinitroethene (FOX-7) an insensitive high-energetic compound, has rarely been reported previously with respect to combustion performance. In order to quickly apply it to propellants, the thermal decomposition behaviors of FOX-7 should be optimized. Metal complexes of nano-graphene oxide have an obvious effect on the thermal decomposition of energy materials. In this paper, the metal (Cu and Fe) complexes of nano-graphene oxide (nGO) have been synthesized using nGO as a ligand and metal ions as a coordination center. They were mixed with FOX-7 as additives to form energetic composites, and the chemical bond distributions and thermal decomposition processes of these composites have been investigated. The results show that Cu and Fe are uniformly distributed on the surface of the nGO. The thermal decomposition processes of nGO-metal-FOX-7 composites have been fully characterized by Differential scanning calorimeter (DSC) and Thermal gravimetric analyzer-Differential scanning calorimeter-Infrared spectroscopy-Mass spectrum (TG-DSC-IR-MS) coupling technology. The results show that the Fe based complex affect the decomposition of FOX-7 than the Cu based one with the initial decomposition temperature of 230 °C and the apparent heat release of 3535.6 J·g. Moreover, the addition of nGO-metal complexes could promote the formation of nitrogen during the decomposition of FOX-7, indicating a more complete decomposition.
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http://dx.doi.org/10.3390/nano10010144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023237PMC
January 2020

Radiation-induced lung injury patterns and the misdiagnosis after SBRT of lung cancer.

Eur J Radiol 2019 Dec 21;121:108708. Epub 2019 Oct 21.

Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China. Electronic address:

Purpose: To analyze radiation-induced lung injury (RIL) after stereotactic body radiotherapy (SBRT) of lung cancer and the subsequent clinical problems.

Methods: 106 lung cancer patients treated with SBRT were included, their computed tomography (CT) scans were reviewed. Late injury pattern was classified by Koening's, radiologist' diagnosis reports for RIL was reviewed. Logistic regression was used to analyze the predictive model of injury pattern, which was also validated by ROC curve.

Results: Radiographic late injury within at least 6 months after SBRT was concluded. The majority of late RIL was mass-like pattern, not the modified conventional pattern. 36.8% patients showed acute injury, which trend to occur late lung injury earlier than patients who were not found acute injury (p =  0.0185). 24.5% RIL cases were misdiagnosed to tumor progression by radiologists. Most misdiagnosis occurred among mass-like pattern. Per fraction dose (p < 0.0001), prescription isodose line (p =  0.027) and age (p =  0.089) trend to associate with the occurrence of mass-like injury pattern. Nomogram was established based on these parameters, ROC curve showed that area under the ROC curve (AUC) of the nomogram was 0.767 (95% CI = 0.677-0.857), which was better than any factors along.

Conclusion: SBRT for lung cancer patients was safe, the majority of late RIL was mass-like pattern. This injury was difficult to be distinguished from tumor progression, which leaded to misdiagnosis of 24.5% patients receiving SBRT. A nomogram based on age, per fraction dose and the prescription isodose line may assist the diagnosis in clinical practice.
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http://dx.doi.org/10.1016/j.ejrad.2019.108708DOI Listing
December 2019

Expression and prognostic value of FOXP1 in esophageal squamous cell carcinoma.

Pathol Res Pract 2019 Dec 23;215(12):152645. Epub 2019 Oct 23.

Department of Pathology Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address:

Background: Forkhead box protein P1 (FOXP1) has been suggested as a prognostic marker in several malignant tumors. However, the significance of FOXP1 in esophageal squamous cell carcinoma (ESCC) is still unclear. The purpose of this study was to investigate the expression pattern of FOXP1 in normal esophageal tissue and ESCC and to analyze the clinicopathological significance and prognostic value of FOXP1 in ESCC.

Methods: FOXP1 was detected by immunohistochemistry using tissue microarrays containing tumor tissues and adjacent normal tissues from 270 ESCC patients with oncological follow-up data.

Results: Normal esophageal tissues predominantly showed an exclusive nuclear FOXP1 (n-FOXP1) expression pattern, and no exclusive cytoplasmic FOXP1 (c-FOXP1) staining was found. In ESCC, the expression rates of exclusive n-FOXP1-positive, exclusive c-FOXP1-positive, both nuclear and cytoplasmic positive and complete negative were 14.4%, 28.9%, 10.4% and 46.3%, respectively. High n-FOXP1 expression was significantly correlated with decreased postoperative recurrence and distant metastasis (P < 0.05). Furthermore, elevated c-FOXP1 expression was significantly associated with regional lymph node metastasis and distant metastasis (P < 0.05). High c-FOXP1 expression had an effect on shorter overall survival (OS) time, but the difference was not statistically significant (P > 0.05). Kaplan-Meier analysis showed that ESCC patients with high n-FOXP1 expression survived significantly longer than patients with low n-FOXP1 expression. Multivariate analysis confirmed that patients with high n-FOXP1 staining exhibit good prognosis and n-FOXP1 was an independent factor for ESCC prognosis.

Conclusions: Our results suggest that FOXP1 plays an essential role in ESCC progression and prognosis and may be a useful biomarker for predicting survival.
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http://dx.doi.org/10.1016/j.prp.2019.152645DOI Listing
December 2019

Superhydrophobic and superaerophilic hierarchical Pt@MIL-101/PVDF composite for hydrogen water isotope exchange reactions.

J Hazard Mater 2019 12 16;380:120904. Epub 2019 Jul 16.

Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, P.O. Box 919-226, Mianyang, Sichuan, 621900, China. Electronic address:

A hierarchical porous composite of Pt@MIL-101/ployvinylidene fluoride (Pt@MIL-101/PVDF) was successfully prepared through a solution-processed method. This composite possesses advanced superhydrophobic and superaerophilic performance which makes it a promising catalyst facilitating liquid phase catalytic exchange techniques (LPCE) in hydrogen-water isotope exchange process. Its superhydrophobic property results in the repellence of water drops from flooding the catalytic surface with a relatively large contact angle in the exchange reaction, and its superaerophilic surface broke hydrogen bubbles into thin film so as to reach higher catalytic reactive efficiency. High reactivity and long-term stability in the reaction process can also be achieved by the configuration of mesoporous cages of MIL-101 confining Pt nanoparticles and preventing them from sintering.
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http://dx.doi.org/10.1016/j.jhazmat.2019.120904DOI Listing
December 2019

Icariin-mediated activation of autophagy confers protective effect on rotenone induced neurotoxicity in vivo and in vitro.

Toxicol Rep 2019 25;6:637-644. Epub 2019 Jun 25.

Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, Guizhou, China.

Rotenone (ROT) is an environmental neurotoxin which has been demonstrated to cause characteristic loss of dopamine (DA) neurons in Parkinson's disease (PD). Icariin (ICA) is a flavonoid glucoside isolated from Herba Epimedii that has been shown to display neuroprotective functions. The present study evaluated protective effects of ICA on ROT-induced neurotoxicity and determined the modulation of ICA on the regulation of autophagy in vivo and in vitro. Rats were treated with ROT (1.0 mg/kg/day) with a co-administration of ICA (15 or 30 mg/kg/day) for 5 weeks. Immunohistochemical analysis showed a significant loss in DA neurons in the substantia nigra (SN) of rats treated with ROT, accompanied by an increase in the accumulation of α-synuclein and a compromised mitochondrial respiration. However, co-administration of ICA potently ameliorated the ROT-induced neuronal cell injury and improved mitochondrial function and decreased the accumulation of α-synuclein. ROT treatment resulted in a decrease in the protein expression of LC3-II and Beclin-1, and an increase in the protein level of P62, and upregulated the activation of mammalian target of rapamycin (mTOR), whereas ICA significantly reversed these aberrant changes caused by ROT. Furthermore, the neuroprotective effect of ICA was further verified in PC12 cells. Cells treated with ROT displayed an increased cytotoxicity and a decreased oxygen consumption which were rescued by the presence of ICA. Furthermore, ROT decreased the protein expression level of LC3-II, enhanced Beclin-1 expression, and activated phosphorylation of mTOR, whereas ICA markedly reversed this dysregulation of autophagy caused by ROT in the PC12 cells. Collectively, these results suggest that ICA mediated activation of autophagic flux confers a neuroprotective action on ROT-induced neurotoxicity.
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http://dx.doi.org/10.1016/j.toxrep.2019.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624214PMC
June 2019

Icariin protects rotenone-induced neurotoxicity through induction of SIRT3.

Toxicol Appl Pharmacol 2019 09 25;379:114639. Epub 2019 Jun 25.

Joint International Research Laboratory of Ethnomedicine, Zunyi Medical University, Zunyi, Guizhou, China; Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China; Department of Environmental Health, Indiana University, Bloomington, IN, USA. Electronic address:

Sirtuin-3 (SIRT3) is a mitochondrial NAD + -dependent deacetylase that is essential in regulating mitochondrial proteins and maintaining cellular antioxidant properties. It has been reported that icariin (ICA) is neuroprotective over various neurotoxicant induced oxidative stress. This study aimed to determine whether ICA exerts neuroprotective effects on rotenone (ROT)-induced neurotoxicity through activation of SIRT3. Rats treated with ROT exhibited a marked loss of dopamine (DA) neurons and a decline in motor function, along with a decrease in protein expressions of SIRT3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the substantia nigra (SN). Administration of ICA significantly alleviated the loss of DA neurons, improved behavioral function, and concomitantly enhanced SIRT3 and PGC-1α expressions. The neuroprotective effect of ICA on ROT-induced cytotoxicity was further confirmed in the PC12 cell model, which showed significant improvement in the survival of ROT-treated cells with ICA pretreatment. The cytoprotective effect of ICA was abolished in ROT-treated cells by SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), along with a resultant decrease in PGC-1α expression. In addition, knockdown of PGC-1α by siRNA suppressed ICA-mediated protective effects but did not affect SIRT3 expression, indicating the role of regulation of PGC-1α by SIRT3 in the protective action of ICA. Furthermore, we showed that ICA improved mitochondrial respiration, oxidative status, enhanced antioxidant enzyme SOD activity and GSH/GSSG ratio in cells treated with ROT. However, these protective effects of ICA on ROT-treated cells was markedly abolished by SIRT3 inhibitor 3-TYP. Our findings demonstrate that ICA exerts a neuroprotective role through upregulation of SIRT3.
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http://dx.doi.org/10.1016/j.taap.2019.114639DOI Listing
September 2019

Design of a test bench for gas leaks using CFD simulation and IR-thermography detection.

Environ Technol 2021 Jan 5;42(4):531-544. Epub 2019 Jul 5.

Xi'an Modern Chemistry Research Institute, Xi'an, People's Republic of China.

A test bench was constructed to enable the study of the influence of different parameters for gas leaks using computational fluid dynamics (CFD) simulation and IR-thermography detection. The results show that the gas chamber should be larger than 300×300×300 mm. The diameter of fan-sizing should be 100 mm. However, the influence is not obvious when the temperature changes. Meanwhile, the influence of the geometry of flow disturbance objects is shown by a sphere and cubic type to be obvious. Based on the results of simulation and detection, a schematic diagram for gas leaks is designed. The parameters of the test bench are also confirmed. The simulated and designed test bench can be used to test gas leaks by IR-thermography in future research.
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http://dx.doi.org/10.1080/09593330.2019.1636144DOI Listing
January 2021

Predicting the Value of Adjuvant Therapy in Esophageal Squamous Cell Carcinoma by Combining the Total Number of Examined Lymph Nodes with the Positive Lymph Node Ratio.

Ann Surg Oncol 2019 Aug 11;26(8):2367-2374. Epub 2019 Jun 11.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: The value of adjuvant therapy for esophageal squamous cell carcinoma (ESCC) has been controversial, at least partially due to the lack of efficient criteria for selecting suitable patients. This study aimed to explore the existence of parameters related to lymph node (LN) status that can predict the value of adjuvant therapy in ESCC.

Methods: The study included 298 patients with ESCC who had undergone radical esophagectomy with lymphadenectomy. Adjuvant therapy was defined as reception of adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. For the study, LN ratio (LNR), total number of resected LNs (TLNs), and pN stage were selected for Cox regression analyses, including their correlations and prognostic values for survival. Log-rank tests were used to compare the survival rates of the patients with and without adjuvant therapy stratified by pN stage, TLNs, LNR, or their combinations.

Results: The independent prognostic factors for survival were TLNs, LNR, and pN stage. Whereas pN stage was significantly related to TLNs and LNR, TLNs were not correlated with LNR. The survival rates between the patients with and those without adjuvant therapy stratified by pN stage, TLNs, or LNR did not differ significantly. We used the median values of TLNs and LNR to group the patients into four groups. The patients in the group with fewer TLNs and higher LNR who had undergone adjuvant therapy showed a significantly better survival than those without adjuvant therapy (p = 0.030).

Conclusions: In contrast to TLNs, LNR, and pN stage as single factors, the combination of TLNs and LNR can predict the value of adjuvant therapy.
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http://dx.doi.org/10.1245/s10434-019-07489-3DOI Listing
August 2019

A knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation.

Biochem Biophys Res Commun 2019 07 30;515(2):359-365. Epub 2019 May 30.

Institute of Developmental Biology, School of Life Science, Shandong University, Jinan, Shandong, China. Electronic address:

SLC26A4 gene mutations lead to Pendred syndrome and non-syndromic hearing loss (DFNB4). The mouse model is well used to study the pathology of Pendred syndrome, however, mice with different Slc26a4 mutations exhibit different phenotypes, and these mice have severe deafness and inner ear malformations that are not imitated less severely Human phenotype. In this study, we generated a knock-in mouse model of Pendred syndrome with Slc26a4 L236P mutation to mimic the most common mutation found in human. Some L236P mice were observed to have significant vestibular dysfunction including torticollis and circling, the giant otoconia and destruction of the otoconial membrane was observed in L236P mice. Unlike other profoundly deafness in Slc26a4 mouse model, L236P mice present mild to profound hearing loss, consistent with the hearing threshold, inner ear hair cells also lost from slight to significant. Together, these data demonstrate that the L236P mouse phenotype is more similar to the human phenotype and should be used as a tool for further research into the human Pendred syndrome.
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http://dx.doi.org/10.1016/j.bbrc.2019.05.157DOI Listing
July 2019

microRNA-messenger RNA regulatory network of esophageal squamous cell carcinoma and the identification of miR-1 as a biomarker of patient survival.

J Cell Biochem 2019 08 24;120(8):12259-12272. Epub 2019 Apr 24.

Department of Pathology Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Emerging evidence indicates that microRNAs (miRNAs) play an important role in tumor carcinogenesis and progression by targeting gene expression. The goal of this study was to comprehensively analyze the vital functional miRNAs and their target genes in esophageal squamous cell carcinoma (ESCC) and to explore the clinical significance and mechanisms of miR-1 in ESCC. First, the miRNA and messenger RNA (mRNA) expression profiles of ESCC were determined with microarray technology. Using an integrated analysis of miRNAs and their target genes with multistep bioinformatics methods, the miRNA-mRNA regulatory network in ESCC was constructed. Next, miR-1 expression in 292 ESCC patients and its relationship with clinicopathological features and prognosis were detected by in situ hybridization. Furthermore, the biological functions of miR-1 were determined with in vitro and in vivo functional experiments. Finally, real-time quantitative reverse transcription polymerase chain reaction, Western blot analysis, and luciferase reporter assays were performed to verify the target genes of miR-1. In this study, 67 miRNAs and 2992 genes were significantly differentially expressed in ESCC tissues compared with their expression in adjacent normal tissues, and an miRNA-mRNA regulatory network comprising 59 miRNAs and 162 target mRNAs was identified. Low miR-1 expression was correlated with pathological T stage, lymph node metastasis, vessel invasion, and poor clinical outcome. miR-1 suppressed ESCC cell proliferation and invasion and promoted ESCC cell apoptosis. Fibronectin 1 (FN1) was verified as a direct target of miR-1. Taken together, the present results suggest that miR-1 may be a valuable prognostic predictor for ESCC, and the miR-1/FN1 axis may be a therapeutic target.
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http://dx.doi.org/10.1002/jcb.28166DOI Listing
August 2019

Deletion of Brg1 causes stereocilia bundle fusion and cuticular plate loss in vestibular hair cells.

Hear Res 2019 06 8;377:247-259. Epub 2019 Apr 8.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, 250100, China. Electronic address:

Brg1 is an ATPase subunit of the SWI/SNF chromatin-remodeling complex, and it is indispensable for the development and homeostasis of various organs. Conditional deletion of Brg1 in cochlea hair cells (HCs) leads to multiple structural defects and profound deafness. However, the premature death of Brg1-deficient cochlea HCs hindered further study of the role of Brg1. In contrast to cochlea HCs, Brg1-deficient vestibular HCs survived for a long time. Therefore, HC apical structure and vestibular function were examined in inner HC-specific conditional Brg1 knockout mice. Vestibular HCs exhibited fused and elongated stereocilia bundles after deletion of Brg1, and the cuticular plate was absent in most HCs with fused stereocilia bundles. HC loss was observed in conditional Brg1 knockout mice at the age of 12 months. Morphological defects and HC loss were primarily restricted in the striolar region of the utricle and saccule and in the central region of ampulla. The behavioral tests revealed that Brg1 deletion in HCs caused vestibular dysfunction in older adult mice. These results suggest that Brg1 may play specific roles in the maintenance of the HC stereocilia bundle and the cuticular plate.
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http://dx.doi.org/10.1016/j.heares.2019.04.002DOI Listing
June 2019

Transformation of Combustion Nanocatalysts inside Solid Rocket Motor under Various Pressures.

Nanomaterials (Basel) 2019 Mar 6;9(3). Epub 2019 Mar 6.

Science and Technology on Combustion, Internal Flow and Thermo-structure Laboratory, Northwestern Polytechnical University, Xi'an 710072, China.

In this paper, the dependences of the morphology, particle sizes, and compositions of the condensed combustion products (CCP) of modified double-base propellants (1,3,5-trimethylenetrinitramine (RDX) as oxidizer) on the chamber pressure (<35 MPa) and nickel inclusion have been evaluated under a practical rocket motor operation. It has been shown that higher pressure results in smaller average particle sizes of the CCPs. The CCPs of Ni-containing propellants have more diverse morphologies, including spherical particles, large layered structures, and small flakes coated on large particles depending on the pressure. The specific surface area (SSA) of CCPs is in the range of 2.49 to 3.24 m² g for propellants without nickel are less dependent on the pressure, whereas it is 1.22 to 3.81 Ni-based propellants. The C, N, O, Al, Cu, Pb, and Si are the major elements presented on the surfaces of the CCP particles of both propellants. The compositions of CCPs from Ni-propellant are much more diverse than another one, but only three or four major phases have been found for both propellants under any pressure. The metallic copper is presented in CCPs for both propellants when the chamber pressure is low. The lead salt as the catalyst has been transformed in to Pb(OH)Cl as the most common products of lead-based catalysts with pressure lower than 15 MPa. When pressure is higher than 5 MPa, the nickel-based CCPs has been found to contain one of the following crystalline phases: Pb₂Ni(NO₂)₆, (NH₄)₂Ni(SO₄)₂·6H₂O, C₂H₂NiO₄·2H₂O, and NiO, depending on the pressure.
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http://dx.doi.org/10.3390/nano9030381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473950PMC
March 2019

Desensitizing Effect of Graphene Oxide on Thermolysis Mechanisms of 4,4'-Azo-1,2,4-triazole Studied by Reactive Molecular Dynamics Simulations.

J Phys Chem A 2019 Feb 6;123(7):1285-1294. Epub 2019 Feb 6.

Key Laboratory of Applied Surface and Colloid Chemistry, MOE/School of Chemistry and Chemical Engineering , Shaanxi Normal University , Xi'an 710062 , China.

Graphene oxide (GO) has obvious desensitizing effect on the thermal decomposition of energetic materials such as HMX, CL-20, etc. 4,4'-Azo-1,2,4-triazole (ATRZ) is known as a new type of energetic material with high N content; the underlying thermal decomposition mechanism of graphene oxide-ATRZ (GO-ATRZ) complex with low sensitivity has not been studied. The present work studies the thermal decomposition mechanisms of GO, ATRZ,and the GO-ATRZ complex (the number of carboxyl groups on GO:ATRZ = 2:1) by the ReaxFF molecular reactive dynamic simulations and kinetics calculations. As a result, it has been found that the main decomposition pathway of GO is the exfoliation of hydroxyl and carboxyl groups on the graphene sheet, whereas ATRZ breaks its five-membered ring as the main decomposition path, and the ring further decomposes into small molecules, such as CHN, N, HN, HN, etc. The major effect of GO on ATRZ is probably derived from the stable graphene sheet, which has a space effect on ATRZ, and the strong oxidizing hydroxyl groups produced during GO decomposition, which results in the formation of CON and CHON. By calculating the activation energy of N generation in the reactions, it can be concluded that the addition of GO can increase the decomposition activation energy of ATRZ (41.1 kJ·mol) in comparison with that of its pure substance (25.0 kJ·mol). Therefore, GO can be combined with ATRZ as a desensitizer where GO can improve the molecular stability of ATRZ.
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http://dx.doi.org/10.1021/acs.jpca.8b10087DOI Listing
February 2019

Implementation strategy of a CNN model affects the performance of CT assessment of EGFR mutation status in lung cancer patients.

IEEE Access 2019 13;7:64583-64591. Epub 2019 May 13.

Department of Radiology, Columbia University Medical Center, NY 10032 USA.

Objective: To compare CNN models implemented using different strategies in the CT assessment of EGFR mutation status in patients with lung adenocarcinoma.

Methods: 1,010 consecutive lung adenocarcinoma patients with known EGFR mutation status were randomly divided into a training set (n=810) and a testing set (n=200). CNN models were constructed based on ResNet-101 architecture but implemented using different strategies: dimension filters (2D/3D), input sizes (small/middle/large and their fusion), slicing methods (transverse plane only and arbitrary multi-view planes), and training approaches (from scratch and fine-tuning a pre-trained CNN). The performance of the CNN models was compared using AUC.

Results: The fusion approach yielded consistently better performance than other input sizes, although the effect often did not reach statistical significance. Multi-view slicing was significantly superior to the transverse method when fine-tuning a pre-trained 2D CNN but not a CNN trained from scratch. The 3D CNN was significantly better than the 2D transverse plane method but only marginally better than the multi-view slicing method when trained from scratch. The highest performance (AUC=0.838) was achieved for the fine-tuned 2D CNN model when built using the fusion input size and multi-view slicing method.

Conclusion: The assessment of EGFR mutation status in patients is more accurate when CNN models use more spatial information and are fine-tuned by transfer learning. Our finding about implementation strategy of a CNN model could be a guidance to other medical 3D images applications. Compared with other published studies which used medical images to identify EGFR mutation status, our CNN model achieved the best performance in a biggest patient cohort.
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http://dx.doi.org/10.1109/access.2019.2916557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500487PMC
May 2019

Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.

J Clin Invest 2018 11 24;128(11):4938-4955. Epub 2018 Sep 24.

School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.

The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.
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http://dx.doi.org/10.1172/JCI98058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205401PMC
November 2018