Publications by authors named "Yi Xie"

1,054 Publications

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Combinatorial deployment of F-actin regulators to build complex 3D actin structures .

Elife 2021 May 5;10. Epub 2021 May 5.

Biological Sciences, University of Denver, Denver, United States.

Despite extensive studies on the actin regulators that direct microfilament dynamics, how these regulators are combinatorially utilized in organismal tissues to generate 3D structures is an unresolved question. Here, we present an in-depth characterization of cortical actin cap dynamics and their regulation . We identify rapid phases of initiation, expansion, duplication and disassembly and examine the functions of 7 different Actin and/or Nucleator Regulators (ANRPs) in guiding these behaviors. We find ANRPs provide distinct activities in building actin cap morphologies - specifically, while DPod1 is a major regulator of actin intensities, Cortactin is required for continued cortical growth, while Coronin functions in both growth and intensity and is required for Cortactin localization to the cap periphery. Unexpectedly, cortical actin populations recover after regulator disruption, suggestive of a deep competition for limited G-actin pools, and we measure Arp2/3 recruitment efficiencies through an ectopic relocalization strategy. Our results illustrate how the coordination of multiple actin regulators can orchestrate organized and dynamic actin structures in a developmental system.
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http://dx.doi.org/10.7554/eLife.63046DOI Listing
May 2021

Association between malnutrition and long-term mortality in older adults with ischemic stroke.

Clin Nutr 2021 Apr 21;40(5):2535-2542. Epub 2021 Apr 21.

Department of Neurology, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, China; Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China; Stroke Center & Department of Neurology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, Anhui, China; Department of Neurology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, China. Electronic address:

Background & Aims: Malnutrition is associated with poor prognosis of different diseases. This study aimed to investigate the association of malnutrition with long-term mortality of older adults with ischemic stroke in China.

Methods: We selected patients aged ≥65 years with first-ever ischemic stroke from the Nanjing Stroke Registry Program. Malnutrition was defined according to the controlling nutritional status score (CONUT), the geriatric nutritional risk index (GNRI), and the prognostic nutritional index score (PNI), respectively. Multivariable Cox proportional hazards regressions and competing risk regressions were performed to explore the relationship between malnutrition and the risk of mortality in older adults with ischemic stroke.

Results: Among 1065 enrolled patients, 60.5%, 46.7%, and 30.6% of patients were malnourished according to CONUT, GNRI, and PNI score. During a median follow-up of 4.74 (3.73-5.82) years, 205 (19.2%) patients died. In multivariate analysis, malnutrition (severe risk versus normal nutrition) was associated with significantly increased risk for mortality by the CONUT (adjusted hazard ratio [HR] 4.615, 95% confidence interval [CI] 1.373-15.514, P = 0.013), GNRI (adjusted HR 3.641, 95% CI 1.924-6.891, P < 0.001), and PNI score (adjusted HR 1.587, 95% CI, 1.096-2.297, P = 0.014). Furthermore, adding the malnutrition indexes to models modestly improved the predictive ability of mortality.

Conclusions: Our study indicated that malnutrition was highly prevalent in older Chinese adults with ischemic stroke and associated with increased mortality. Further research is required to evaluate the efficacy of nutritional management in these patients.
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http://dx.doi.org/10.1016/j.clnu.2021.04.018DOI Listing
April 2021

Efficient Photooxidation of Methane to Liquid Oxygenates over ZnO Nanosheets at Atmospheric Pressure and Near Room Temperature.

Nano Lett 2021 Apr 29. Epub 2021 Apr 29.

Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230026, P. R. China.

Direct CH photoconversion into liquid oxygenates under mild conditions still represents a huge challenge. Herein, two-dimensional oxide semiconductors are designed to generate abundant active O species for activating C-H bond of methane. Taking the synthetic ZnO nanosheets as an example, in situ electron paramagnetic resonance spectra verified their lattice oxygen atoms could capture photoexcited holes and generate active O species, which could efficiently abstract H from CH to generate ·CH radicals. Gibbs free energy calculations and in situ Fourier-transform infrared spectroscopy corroborated the rate-limiting step was the first C-H bond activation process, whereas the exoergic oxidation of *CHO to HCOOH was easier than the endoergic overoxidation to CO, accounting for the selective production of liquid oxygenates. As a result, the formation rate of liquid oxygenates over ZnO nanosheets reached 2.21 mmol g h with a selectivity of 90.7% at atmospheric pressure and approximately 50 °C, outperforming previously reported photocatalysts under similar conditions.
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http://dx.doi.org/10.1021/acs.nanolett.1c01204DOI Listing
April 2021

Cediranib Induces Apoptosis, G1 Phase Cell Cycle Arrest, and Autophagy in Non-Small-Cell Lung Cancer Cell A549 In Vitro.

Biomed Res Int 2021 29;2021:5582648. Epub 2021 Mar 29.

Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, Guangdong 516029, China.

Lung cancer remains the leading cause of cancer death worldwide. Late diagnosis, chemoresistance, and metastasis are the main reasons for the high mortality rate of lung cancer. Therefore, the development of other treatments is urgent. Cediranib (CED), a vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, shows promising antitumour activities in various cancers including lung cancer. Here, we explored the effects and the underlying molecular mechanism of CED on non-small-cell lung cancer (NSCLC) cell line A549 cells in vitro. Our results show that CED could inhibit A549 cell proliferation and cloning formation. Meanwhile, G1 phase cell cycle arrest was also found, as featured by the increased proportion of G1 phase cells as well as the reduction of G1 phase relative proteins CDK4/cyclin D1 and CDK2/cyclin E. Moreover, the ratio of LC3-II/LC3-I was elevated significantly in CED-treated groups compared with the controls. Furthermore, the expression of p-Akt, p-P38, p-Erk1/2, and p-mTOR proteins was decreased obviously in the treatment groups. These results suggest that CED could induce apoptosis and G1 phase cell cycle arrest in A549 cells. Meanwhile, CED may induce autophagy through MAPK/Erk1/2 and Akt/mTOR signal pathway in A549 cells.
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http://dx.doi.org/10.1155/2021/5582648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024085PMC
March 2021

MicroRNA-520a Suppresses Pathogenesis and Progression of Non-Small-Cell Lung Cancer through Targeting the RRM2/Wnt Axis.

Anal Cell Pathol (Amst) 2021 30;2021:9652420. Epub 2021 Mar 30.

Department of Tuberculosis, Shandong Provincial Chest Hospital, Jinan, 250013 Shandong, China.

MicroRNAs (miRNAs) regulate multiple cellular behaviors, and their aberrant expression is frequently associated with disease progression. This research focused on the effects of miR-520a on the development of non-small-cell lung cancer (NSCLC) and the molecules involved. Tumor and normal tissues from 24 patients with NSCLC were collected. Differentially expressed miRNAs between tumor tissues and normal tissues were screened using microarrays, and miR-520a was screened to be significantly poorly expressed in tumor samples. Artificial upregulation of miR-520a reduced proliferation, migration and invasion, and resistance to death of NSCLC A549 and H460 cells according to the MTT, EdU labeling, transwell, and flow cytometry assays, respectively. miR-520a upregulation suppressed growth and metastasis of xenograft tumors in vivo. The integrated bioinformatic analysis and dual luciferase assays suggested that miR-520a targeted ribonucleotide reductase subunit 2 (RRM2) mRNA and inactivated the Wnt/-catenin signaling pathway in NSCLC cells. Upregulation of RRM2 enhanced the malignant behaviors of NSCLCs, but the oncogenic effects of RRM2 were blocked upon miR-520a overexpression. To conclude, this study evidenced that miR-520a inhibits NSCLC progression through suppressing RRM2 and the Wnt signaling pathway. This paper may offer novel insights into NSCLC treatment.
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http://dx.doi.org/10.1155/2021/9652420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026327PMC
March 2021

A Follow-Up Study of Respiratory and Physical Functions After Discharge in re-detectable positive SARS-CoV-2 nucleic acid results in Recovered COVID-19 Patients.

Int J Infect Dis 2021 Apr 12. Epub 2021 Apr 12.

Department of Respiratory Medicine, Tianjin Haihe Hospital, 300350, China; Tianjin Institute of Respiratory Diseases, Tianjin 300350, China. Electronic address:

Objective: This study aimed to evaluate the respiratory and physical functions of patients who retested positive for SARS-CoV-2 RNA during post-COVID-19 rehabilitation.

Methods: A total of 302 discharged COVID-19 patients were included. Discharged patients were followed up for 14 days to 6 months. The modified Medical Research Council (mMRC) dyspnea scale, Borg rating of perceived exertion, and manual muscle testing (MMT) scores on day 14 and at 6 months after discharge were compared between the re-detectable positive (RP) and non-RP (NRP) groups. Prognoses of respiratory and physical functions were compared between patients who recovered from moderate and severe COVID-19.

Results: Of the patients, 7.6% were RP. The proportion of patients who used antiviral drugs was significantly lower in the RP group than in the NRP group. There were no differences in the mMRC, Borg, and MMT scores within the RP group and the NRP group. The mMRC, Borg, and MMT scores were worse for severe-type cases than for moderate-type cases at both follow-ups.

Conclusion: COVID-19 patients who did not take antiviral drugs were more likely to be RP after discharge. However, respiratory and physical function recovery were not related to re-positivity during rehabilitation but to disease severity during hospitalization.
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http://dx.doi.org/10.1016/j.ijid.2021.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056475PMC
April 2021

Conversion of Waste Plastics into Value-Added Carbonaceous Fuels under Mild Conditions.

Adv Mater 2021 Apr 8:e2005192. Epub 2021 Apr 8.

Hefei National Laboratory for Physical Science at Microscale, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.

Owing to the extremely difficult breakage of the adamant cross-linked structures, converting non-recyclable plastic wastes into valuable fuels usually demands rigorous conditions, wherein the required high temperature and pressure is inevitably energy-wasting and environment-polluting. Given this aspect, herein, the recent achievements in the conversion of plastics into value-added carbonaceous fuels under mild conditions are summarized. In detail, solar-driven conversion of commercial plastics into liquid fuels in alkaline solutions or pure water at ambient temperature and pressure are surveyed; also, enzyme-driven conversion of polyethylene terephthalate into terephthalic acid and ethylene glycol at a mild temperature are emphasized; and low-temperature-driven catalytic conversion of polyethylene into oils and waxes with the help of a light alkane are reviewed. Finally, other potentially used strategies and in situ characterization technologies in plastics degradation under moderate conditions are presented.
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http://dx.doi.org/10.1002/adma.202005192DOI Listing
April 2021

Exciton-Mediated Energy Transfer in Heterojunction Enables Infrared Light Photocatalysis.

Angew Chem Int Ed Engl 2021 Apr 7. Epub 2021 Apr 7.

Hefei National Laboratory for Physical Sciences at the Microscale, CAS Centre for Excellence in Nanoscience, University of Science and Technology of China, Hefei, 230026, China.

Although a few semiconductors can directly absorb infrared light, their intrinsic properties like improper band-edge position and strong electron-hole interaction restrict further photocatalytic applications. Herein, we propose an exciton-mediated energy transfer strategy for realizing efficient infrared light response in heterostructures. Using black phosphorous/polymeric carbon nitride (BP/CN) heterojunction, CN could be indirectly excited by infrared light with the aid of nonradiatively exciton-based energy transfer from BP. At the same time, excitons are dissociated into free charge carriers at the interface of BP/CN heterojunction, followed by hole injection to BP and electron retainment in CN. As a result of these unique photoexcitation processes, BP/CN heterojunction exhibits promoted conversion rate and selectivity in amine-amine oxidative coupling reaction even under infrared light irradiation. This study opens a new way for the design of efficient infrared light activating photocatalysts.
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http://dx.doi.org/10.1002/anie.202101090DOI Listing
April 2021

Multi-Scale Feature Pyramid Network: A Heavily Occluded Pedestrian Detection Network Based on ResNet.

Sensors (Basel) 2021 Mar 5;21(5). Epub 2021 Mar 5.

School of Electronic and Information Engineering, Beijing Jiaotong University, Beijing 100044, China.

The existing pedestrian detection algorithms cannot effectively extract features of heavily occluded targets which results in lower detection accuracy. To solve the heavy occlusion in crowds, we propose a multi-scale feature pyramid network based on ResNet (MFPN) to enhance the features of occluded targets and improve the detection accuracy. MFPN includes two modules, namely double feature pyramid network (FPN) integrated with ResNet (DFR) and repulsion loss of minimum (RLM). We propose the double FPN which improves the architecture to further enhance the semantic information and contours of occluded pedestrians, and provide a new way for feature extraction of occluded targets. The features extracted by our network can be more separated and clearer, especially those heavily occluded pedestrians. Repulsion loss is introduced to improve the loss function which can keep predicted boxes away from the ground truths of the unrelated targets. Experiments carried out on the public CrowdHuman dataset, we obtain 90.96% AP which yields the best performance, 5.16% AP gains compared to the FPN-ResNet50 baseline. Compared with the state-of-the-art works, the performance of the pedestrian detection system has been boosted with our method.
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http://dx.doi.org/10.3390/s21051820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961544PMC
March 2021

Ultrastable and Efficient Visible-light-driven CO2 Reduction Triggered by Regenerative Oxygen-vacancies in Bi2O2CO3 Nanosheets.

Angew Chem Int Ed Engl 2021 Mar 30. Epub 2021 Mar 30.

University of Science and Technology of China, hefei national laboratory for physical science at microscale, CHINA.

Surface vacancies can exert positive impact on CO2 photoreduction activity, yet difficultly maintaining long-term stability. Herein, we first design a fast low-pressure ultraviolet light irradiation strategy for easily regenerating the nearly equivalent surface vacancies, thus concurrently optimizing CO2 photoreduction activity and stability. Taking the defective Bi2O2CO3 nanosheets as an example, nearly equal amount of oxygen vacancies can be regenerated under UV light irradiation. Synchrotron-radiation quasi in-situ X-ray photoelectron spectra disclose the Bi sites in the O-defective Bi2O2CO3 nanosheets can act as the highly active sites, which not only help to activate CO2 molecules, but also contribute to stabilizing the rate-limiting COOH* intermediate. Also, in-situ Fourier transform infrared spectroscopy and in-situ mass spectrometry unravel the UV light irradiation contributes to accelerating CO desorption process. As a result, the O-defective Bi2O2CO3 nanosheets achieve a stability up to 2640 h over 110 cycling tests and a high evolution rate of 275 μmol g-1 h-1 for visible-light-driven CO2 reduction to CO. This study offers a new way for developing sustainable CO2 reduction photocatalysts.
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http://dx.doi.org/10.1002/anie.202101894DOI Listing
March 2021

Droplet rolling angle model of micro-nanostructure superhydrophobic coating surface.

Eur Phys J E Soft Matter 2021 Mar 9;44(2):25. Epub 2021 Mar 9.

State Key Laboratory of Silicate Materials for Architectures, Wuhan University of Technology (WUT), Wuhan, 430074, China.

The droplet rolling angle is one of the important indicators to measure the coating's hydrophobic performance, but the specific factors affecting the droplet rolling angle on the micro-nanostructured superhydrophobic coating surface are not yet known. Based on the rolling mechanism of droplets on rough surfaces, and from the perspective of coating microscopic energy conservation, this paper points out that the micron-scale morphology and the nanoscale morphology can comprehensively affect the droplet rolling angle. From the above perspective, a mathematical model of the droplet rolling angle on the micro-nanostructure superhydrophobic coating surface was established. The model shows that the droplet rolling angle is positively correlated with the ratio of nano-sized pillar width to spacing, the ratio of micron-sized papilla radius to spacing, and the liquid-gas interfacial tension, and is negatively correlated to the droplet intrinsic contact angle, droplet volume and droplet density. The droplet rolling angle calculated by the presented model is in good agreement with the experimentally tested results. This model can provide good accuracy in predicting the droplet rolling angle on the micro-nanostructured superhydrophobic coating surface.
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http://dx.doi.org/10.1140/epje/s10189-021-00036-7DOI Listing
March 2021

Inhibition of miR-103-3p Preserves Neurovascular Integrity Through Caveolin-1 in Experimental Subarachnoid Hemorrhage.

Neuroscience 2021 05 17;461:91-101. Epub 2021 Mar 17.

Department of Neurology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Caveolin-1 (Cav-1) is a constitutive structural protein of caveolae in the plasma membrane. It plays an important role in maintaining blood brain barrier (BBB) integrity. In this study, we identified that miR-103-3p, a hypoxia-responsive miRNA, could interact with Cav-1. In endothelial cells, miR-103-3p mimic diminished the expression of Cav-1 and tight junction proteins, which were rescued by the inhibition of miR-103-3p. We found a substantial increase of miR-103-3p and decease of Cav-1 in the rat subarachnoid hemorrhage (SAH) model. Pre-SAH intracerebroventricularly injection of miR-103-3p antagomir relieved Cav-1 loss, sequentially reduced BBB permeability and improved neurological function. Finally, we demonstrated that the salutary effects of miR-103-3p antagomir were abolished in Cav-1 knock-out mice, suggesting that Cav-1 was required for the miR-103-3p inhibition-induced neurovascular protection. Taken together, our findings suggest that the inhibition of miR-103-3p could exert neuroprotective effects through preservation of Cav-1 and BBB integrity, making miR-103-3p a novel therapeutic target for SAH.
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http://dx.doi.org/10.1016/j.neuroscience.2021.03.007DOI Listing
May 2021

Retroperitoneoscopic partial nephrectomy using a 980/1470-nm dual-diode laser for small exophytic renal tumors.

Lasers Med Sci 2021 Mar 13. Epub 2021 Mar 13.

Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Laser-supported laparoscopic partial nephrectomy is a promising new technique, but remains under experiment. We presented our single institutional experience of laparoscopic partial nephrectomy using the 980/1470-nm dual-diode laser system to investigate its feasibility, and oncological and functional outcomes. The study retrospectively evaluated 25 patients with small exophytic renal tumors, who underwent laparoscopic partial nephrectomy using a 980/1470-nm dual-diode laser. The demographics, surgical data, complications, pathological variables, oncological, and functional outcomes were reviewed. The changes in hemoglobin and estimated glomerular filtration rate (eGFR) before and after surgery were statistically analyzed. The investigators operated on a total of 25 patients. The off-clamping technique was performed for 23 cases, while the other two cases required renal artery clamping due to unsatisfactory hemostasis. The tumor diameter was 24.6± 6.2 mm, and the mean operative time was 104.4± 23.4 min. The median estimated intraoperative blood loss (EBL) was 100 ml (range 50-600 ml). No major complications (Clavien-Dindo >II) occurred perioperatively. The mean change in hemoglobin before and after the operation was 9 g/l, with a P value of <0.001. The mean decrease in eGFR from before the surgery to the 6-month follow-up was 1.4 ml/min, with a P value of 0.463. The postoperative histopathology evaluation did not demonstrate a positive surgical margin. No recurrence or metastasis was found during the follow-up (mean 24 months). Laparoscopic partial nephrectomy using a 980/1470 nm dual-diode laser appears to be a feasible and oncological satisfactory technique for the treatment of small renal mass (SRM), with the advantages of reducing warm ischemia time.
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http://dx.doi.org/10.1007/s10103-021-03284-3DOI Listing
March 2021

Selective CO Photoreduction into C Product Enabled by Charge-Polarized Metal Pair Sites.

Nano Lett 2021 Mar 1;21(5):2324-2331. Epub 2021 Mar 1.

Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230026, P. R. China.

Selective CO photoreduction into a high-energy-density C product is still challenging. Here, charge-polarized metal pair sites are designed to trigger C-C coupling through manipulating asymmetric charge distribution on the reduction intermediates. Taking the synthetic partially reduced CoO nanosheets as an example, theoretical calculations unveil the asymmetric charge distribution on surface cobalt sites. The formed charge-polarized cobalt pair sites not only donate electrons to CO molecules but also accelerate the coupling of asymmetric COOH* intermediates through lowering the energy barrier from 0.680 to 0.240 eV, affirmed by quasi X-ray photoelectron spectroscopy and Gibbs free energy calculations. Also, the electron-rich cobalt sites strengthen their interaction with O of the HOOC-CHO* intermediate, which favors the C-O bond cleavage and hence facilitates the rate-limiting CHCOOH desorption process. The partially reduced CoO nanosheets achieve 92.5% selectivity of CHCOOH in simulated air, while the CO-to-CHCOOH conversion ratio is 2.75%, obviously higher than that in pure CO.
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http://dx.doi.org/10.1021/acs.nanolett.1c00383DOI Listing
March 2021

A Follow-Up Study of Lung Function and Chest Computed Tomography at 6 Months after Discharge in Patients with Coronavirus Disease 2019.

Can Respir J 2021 13;2021:6692409. Epub 2021 Feb 13.

Tianjin Institute of Respiratory Diseases, Tianjin 300350, China.

We aimed to investigate changes in pulmonary function and computed tomography (CT) findings in patients with coronavirus disease 2019 (COVID-19) during the recovery period. COVID-19 patients underwent symptom assessment, pulmonary function tests, and high-resolution chest CT 6 months after discharge from the hospital. Of the 54 patients enrolled, 31 and 23 were in the moderate and severe group, respectively. The main symptoms 6 months after discharge were fatigue and exertional dyspnea, experienced by 24.1% and 18.5% of patients, respectively, followed by smell and taste dysfunction (9.3%) and cough (5.6%). One patient dropped out of the pulmonary function tests. Of the remaining 54 patients, 41.5% had pulmonary dysfunction. Specifically, 7.5% presented with restrictive ventilatory dysfunction (forced vital capacity <80% of the predicted value), 18.9% presented with small airway dysfunction, and 32.1% presented with pulmonary diffusion impairment (diffusing capacity for carbon monoxide <80% of the predicted value). Of the 54 patients enrolled, six patients dropped out of the chest CT tests. Eleven of the remaining 48 patients presented with abnormal lung CT findings 6 months after discharge. Patients with residual lung lesions were more common in the severe group (52.6%) than in the moderate group (3.4%); a higher proportion of patients had involvement of both lungs (42.1% vs. 3.4%) in the severe group. The residual lung lesions were mainly ground-glass opacities (20.8%) and linear opacities (14.6%). Semiquantitative visual scoring of the CT findings revealed significantly higher scores in the left, right, and both lungs in the severe group than in the moderate group. COVID-19 patients 6 months after discharge mostly presented with fatigue and exertional dyspnea, and their pulmonary dysfunction was mostly characterized by pulmonary diffusion impairment. As revealed by chest CT, the severe group had a higher prevalence of residual lesions than the moderate group, and the residual lesions mostly manifested as ground-glass opacities and linear opacities.
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http://dx.doi.org/10.1155/2021/6692409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881736PMC
March 2021

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA.

We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.
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http://dx.doi.org/10.3390/cancers13040633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914929PMC
February 2021

Electrostatically Driven Selective Adsorption of Carbon Dioxide over Acetylene in an Ultramicroporous Material.

Angew Chem Int Ed Engl 2021 Apr 10;60(17):9604-9609. Epub 2021 Mar 10.

Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249-0698, USA.

Separating acetylene from carbon dioxide is important but highly challenging owing to their similar physical properties and molecular dimensions. Herein, we report highly efficient electrostatically driven CO /C H separation in an ultramicroporous cadmium nitroprusside (Cd-NP) with compact pore space and complementary electrostatic potential well fitting for CO , thus enabling molecular quadrupole moment recognition of CO over C H . This material shows a high CO /C H uptake ratio of 6.0 as well as remarkable CO /C H selectivity of 85 under ambient conditions with modest CO heat of adsorption. Neutron powder diffraction experiments and molecular simulations revealed that the electrostatic potential compatibility between pore structure and CO allows it to be trapped in a head-on orientation towards the Cd center, whereas the diffusion of C H is electrostatically forbidden. Dynamic breakthrough experiments have validated the separation performance of this compound for CO /C H separation.
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http://dx.doi.org/10.1002/anie.202100584DOI Listing
April 2021

Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Road, Lanzhou 730000, China.

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.
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http://dx.doi.org/10.3390/ijms22020817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830632PMC
January 2021

Effectiveness of ultra-long protocol on in vitro fertilization/intracytoplasmic sperm injection-embryo transfer outcome in infertile women with endometriosis: A systematic review and meta-analysis of randomized controlled trials.

J Obstet Gynaecol Res 2021 Apr 11;47(4):1232-1242. Epub 2021 Jan 11.

Reproductive Medicine Center, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China.

Objective: To evaluate the effectiveness of ultra-long protocol on reproductive and controlled ovarian hyperstimulation outcome in in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in infertile women with endometriosis versus long protocol.

Methods: We retrieved articles without language restrictions in the Elsevier ScienceDirect, Embase, Medline, PubMed, Web of Science, China National Knowledge Infrastructure, Wan Fang Data Knowledge Service Platform and China Science and Technology Journal Database from inception to August 2020. RCTs including the comparison of reproductive outcome of infertile patients with endometriosis who underwent ultra-long protocol and long protocol were selected. Data extraction was conducted using RevMan 5.3.

Results: A total of nine RCTs in compliance with the standard literature were included. This meta-analysis suggested that ultra-long protocol with a 3-month downregulation could increase clinical pregnancy rate of infertile women with endometriosis (RR=1.31, 95% CI:1.11 ~ 1.55, P = 0.002) versus long protocol. However, subgroup analysis found the different protocol provided no significant difference in improving clinical outcomes in patients with different disease stage of endometriosis.

Conclusion: The ultra-long protocol could improve the clinical pregnancy rate of infertile women with endometriosis compared with long protocol with a 3-month downregulation. And ultra-long protocol could be effective to increase the ongoing pregnancy rate compared to long-protocol. But, the efficacy of ultra-long protocol is not different between early and advanced stage of endometriosis.
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http://dx.doi.org/10.1111/jog.14630DOI Listing
April 2021

MACC1 Contributes to the Development of Osteosarcoma Through Regulation of the HGF/c-Met Pathway and Microtubule Stability.

Front Cell Dev Biol 2020 23;8:825. Epub 2020 Dec 23.

Department of Orthopedics, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.

Osteosarcoma (OS) is the most prevalent human bone malignancy, and presents a global annual morbidity of approximately five cases per million. Notably, precise and efficient targeted therapy has become the most promising strategy for the treatment of OS; however, there is still an urgent need for the identification of suitable therapeutic targets. Metastasis-associated in colon cancer 1 (MACC1) was first identified in colon tumors by differential display RT-PCR, and was shown to be involved in the regulation of colon tumor growth and metastasis through the hepatocyte growth factor (HGF)/c-Met signaling pathway. Additionally, MACC1 overexpression has been reported to induce the growth of several types of cancers, including glioblastoma multiforme and gastric cancer. However, whether MACC1 also plays a role in the progression of OS remains unclear. In this study, we found that MACC1 was highly expressed in human OS tissues, as well as in U-2OS and MG-63 cells, when compared with normal tissues and osteoblasts, respectively. Our data further indicated that MACC1 expression was correlated with several clinicopathological features of OS. Through assays, we found that MACC1 depletion markedly suppressed the proliferative ability of both OS cells and endothelial cells, and inhibited the angiogenic capacity of endothelial cells. Similarly, MACC1 depletion inhibited tumor growth, metastasis, and angiogenesis in mice. Mechanistically, we found that MACC1 could bind to the promoter, and enhanced the proliferation of both OS cells and endothelial cells through the HGF/c-Met signaling pathway. Furthermore, we show that MACC1 also promoted angiogenesis by regulating microtubule dynamics, thereby promoting the progression of OS. Our results indicate that MACC1 may be a new and promising therapeutic target for the treatment of OS.
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http://dx.doi.org/10.3389/fcell.2020.00825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793648PMC
December 2020

Intratumoral and Peritumoral Radiomics of Contrast-Enhanced CT for Prediction of Disease-Free Survival and Chemotherapy Response in Stage II/III Gastric Cancer.

Front Oncol 2020 4;10:552270. Epub 2020 Dec 4.

Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan University People's Hospital, Zhengzhou, China.

Background: We evaluated the ability of radiomics based on intratumoral and peritumoral regions on preoperative gastric cancer (GC) contrast-enhanced CT imaging to predict disease-free survival (DFS) and chemotherapy response in stage II/III GC.

Methods: This study enrolled of 739 consecutive stage II/III GC patients. Within the intratumoral and peritumoral regions of CT images, 584 total radiomic features were computed at the portal venous-phase. A radiomics signature (RS) was generated by using support vector machine (SVM) based methods. Univariate and multivariate Cox proportional hazards models and Kaplan-Meier analysis were used to determine the association of the RS and clinicopathological variables with DFS. A radiomics nomogram combining the radiomics signature and clinicopathological findings was constructed for individualized DFS estimation.

Results: The radiomics signature consisted of 26 features and was significantly associated with DFS in both the training and validation sets (both <0.0001). Multivariate analysis showed that the RS was an independent predictor of DFS. The signature had a higher predictive accuracy than TNM stage and single radiomics features and clinicopathological factors. Further analysis showed that stage II/III patients with high scores were more likely to benefit from adjuvant chemotherapy.

Conclusion: The newly developed radiomics signature was a powerful predictor of DFS in GC, and it may predict which patients with stage II and III GC benefit from chemotherapy.
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http://dx.doi.org/10.3389/fonc.2020.552270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794018PMC
December 2020

Hydrogen Sulfide Overproduction Is Involved in Acute Ischemic Cerebral Injury Under Hyperhomocysteinemia.

Front Neurosci 2020 30;14:582851. Epub 2020 Nov 30.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Objectives: This study aimed to identify the involvement of hydrogen sulfide overproduction in acute brain injury under ischemia/reperfusion and hyperhomocysteinemia.

Methods: and experiments were conducted to determine: the effect of sodium hydrosulfide treatment on the human neuroblastoma cell line (SH-SY5Y) under conditions of oxygen and glucose deprivation; the changes of hydrogen sulfide levels, inflammatory factors, energetic metabolism, and mitochondrial function in the brain tissue of rats under either ischemia/reperfusion alone or a combination of ischemia/reperfusion and hyperhomocysteinemia; and the potential mechanism underlying the relationship between homocysteine and these changes through the addition of the related inhibitors. Furthermore, experimental technologies, including western blot, enzyme-linked immunosorbent assay, immunofluorescence, reverse transcription polymerase chain reaction, and flow cytometry, were used.

Results: Our study found that high concentration of sodium hydrosulfide treatment aggravated the decrease in mitochondrial membrane potential, the increase in both mitochondrial permeability transition pore and translocation of cytochrome C, as well as the accumulation of reactive oxygen species in oxygen and glucose deprived SH-SY5Y cells. As a result, neurological deficit appeared in rats with ischemia/reperfusion or ischemia/reperfusion and hyperhomocysteinemia, and a higher water content and larger infarction size of cerebral tissue appeared in rats combined ischemia/reperfusion and hyperhomocysteinemia. Furthermore, alterations in hydrogen sulfide production, inflammatory factors, and mitochondria morphology and function were more evident under the combined ischemia/reperfusion and hyperhomocysteinemia. These changes were, however, alleviated by the addition of inhibitors for CBS, CSE, Hcy, HS, and NF-κB, although at different levels. Finally, we observed a negative relationship between the blockage of: (a) the nuclear factor kappa-B pathway and the levels of cystathionine β-synthase and hydrogen sulfide; and (b) the hydrogen sulfide pathway and the levels of inflammatory factors.

Conclusion: Hydrogen sulfide overproduction and reactive inflammatory response are involved in ischemic cerebral injury under hyperhomocysteinemia. Future studies in this direction are warranted to provide a scientific base for targeted medicine development.
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http://dx.doi.org/10.3389/fnins.2020.582851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793897PMC
November 2020

Ultrasound-Guided Transmuscular Quadratus Lumbar Block Reduces Opioid Consumption after Laparoscopic Partial Nephrectomy.

Chin Med Sci J 2020 Dec;35(4):289-296

Anesthesiology Department, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

Objectives Transmuscular quadratus lumborum block (TQLB) may provide postoperative analgesia in patients undergoing intraperitoneal surgeries. The purpose of this study was to examine the potential efficacy of TQLB among patients undergoing retroperitoneal procedures, such as the laparoscopic partial nephrectomy (LPN). Methods This prospective, randomized, controlled study was conducted from August 2017 to November 2018 at Peking Union Medical College Hospital (Beijing, China). Patients who were scheduled for a LPN, aged 18-70 years old with an ASA physical status score of I - II were randomly assigned to receive either TQLB with 0.6 ml/kg of 0.5% ropivacaine plus general anesthesia (TQLB group) or general anesthesia alone (control group). Patient-controlled intravenous analgesia with morphine was initiated immediately upon surgery completion. The primary outcome was the cumulative consumption of morphine within 8 h after surgery. The secondary outcome included postoperative consumptions of morphine at other time points, pain score at rest and during activity, postoperative nausea and vomitting (PONV), and recovery related parameters. Results Totally 30 patients per group were recruited in the study. The 8 h consumption of morphine was lower in the TQLB group than in the control group (median, 0.023 mg/kg . 0.068 mg/kg, U=207.5, <0.001). No significant differences were observed in postoperative pain scores between the two groups. Patients in the TQLB group had fewer episodes of PONV (20% 47%, =4.8, =0.028) in the first 24 h after surgery and higher scores for quality of recovery (mean, 138.6 131.9, =-2.164, =0.035) 120 h after surgery than the controls. Conclusions TQLB resulted in an opioid-sparing effect during the early postoperative period following LPN, as well as a lower incidence of PONV and improved quality of recovery.
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http://dx.doi.org/10.24920/003759DOI Listing
December 2020

Highly Specific Coordination-Driven Self-Assembly of 2D Heterometallic Metal-Organic Frameworks with Unprecedented Johnson-type () Nonanuclear Zr-Oxocarboxylate Clusters.

J Am Chem Soc 2021 01 4;143(2):657-663. Epub 2021 Jan 4.

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules and State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.

The quest for new and unique polynuclear metal-oxocarboxylate clusters has led to a continual boom of highly connected and robust metal-organic frameworks (MOFs) with intriguing properties. In this work, by virtue of a highly specific coordination-driven cluster rearrangement process of a presynthesized trinuclear zirconocene-based tripodal metallo-pyridine ligand, we realized the preparation of the first two 2D heterometallic MOFs incorporating unprecedented Johnson-type () nonanuclear Zr-oxocarboxylate clusters, as unambiguously uncovered by single-crystal X-ray crystallography. The resultant two charged frameworks feature counteranion-dependent 3,6-c kgd (JMOF-1) and 3,12-c 3,12L4 (JMOF-2) nets that are formed by octahedral and hexagonal prismatic Zr molecular building blocks (MBBs), respectively. In addition, JMOF-2 shows promise for the purification of acetylene from CO and CH, with IAST selectivities of about 12 and 8, respectively, at 298 K and 1 bar, as well as remarkable iodine capture capacity of up to 2.4 g g.
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http://dx.doi.org/10.1021/jacs.0c11881DOI Listing
January 2021

Cognitive Gains of Aerobic Exercise in Patients With Ischemic Cerebrovascular Disorder: A Systematic Review and Meta-Analysis.

Front Cell Dev Biol 2020 18;8:582380. Epub 2020 Dec 18.

Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Cognitive impairment has become an important problem in ischemic cerebrovascular disorder survivors as disease related deaths have been significantly reduced. Aerobic exercise, the most prevalent mode of physical activity, positively contributes to cognition in both healthy population and people with cognitive impairment. However, studies on its associations with cognitive gains in patients with ischemic cerebrovascular disease showed mixed findings. To explore the cognitive effects of aerobic exercise on ischemic cerebrovascular disorder survivors and investigate the possible moderators on exercise benefits. Randomized controlled trials investigating the effects of sole aerobic exercise on cognitive function in population with ischemic intracranial vascular disorder compared to any control group who did not receive the intervention were enrolled in this systematic review and meta-analysis. Four online database (Pubmed, Cochrane Library, Embase, and Web of Science) were searched. The initial search returned 1,522 citations and ultimately 11 studies were included in the systematic review. Analysis of seven studies showed the beneficial but not statistically significant impact of aerobic exercise on global cognitive function (0.13; 95% Cl -0.09 to 0.35; = 0.25). Participants already with cognitive impairment benefited more from this intervention (0.31; 95% Cl 0.07-0.55; = 0.01) and moderate intensity might be the optimal choice (0.34; 95% Cl -0.01 to 0.69; = 0.06). The program duration and initiation time after stroke occurrence did not predict better cognitive outcome. Aerobic exercise was not associated with improvement of processing speed and executive function, the two subdomains of cognitive function. Aerobic exercise may contribute to cognitive gains in survivors of ischemic cerebrovascular disorder, especially for population already with cognitive decline. Our findings suggest that the adoption of moderate intensity aerobic exercise might improve cognition in such population.
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http://dx.doi.org/10.3389/fcell.2020.582380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775417PMC
December 2020

Handedness Inversion of Chiral 3-Aminophenol Formaldehyde Resin Nanotubes Mediated by Metal Coordination.

Angew Chem Int Ed Engl 2021 Mar 25;60(14):7759-7769. Epub 2021 Feb 25.

Hubei Key Laboratory of Advanced Textile Materials & Application, Wuhan Textile University, Yangguang Road 1, Wuhan, 430200, P. R. China.

Precise adjustment of microstructure and handedness of chiral nanomaterials is important to regulate their properties and performance. Herein, helical 3-aminophenol formaldehyde resin (APF) nanotubes and corresponding carbonaceous nanotubes with controllable handedness and optical activity were obtained via an external metal ion-mediated supramolecular co-templating method in an enantiomerically pure template system, in which an appropriate amount of Mn (Co or Ni ) with moderate coordination abilities can reverse the spatial arrangement of the phenylglycine-based amphiphilic template molecules through metal coordination. Different stacking modes of coordination complexes in disparate metal ion systems lead to diverse helical senses (diameter and pitch) of the obtained helical APF. In addition, this coordination mode of metal intervention can be applied to other amine-based helical polymer synthesis systems, which paves the way for the design of high-quality chiral nanomaterials with satisfactory physical parameters and properties.
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http://dx.doi.org/10.1002/anie.202013790DOI Listing
March 2021

Precise Species Identification by Whole-Genome Sequencing of Enterobacter Bloodstream Infection, China.

Emerg Infect Dis 2021 Jan;27(1):161-169

The clinical importance of Enterobacter spp. remains unclear because phenotype-based Enterobacter species identification is unreliable. We performed a genomic study on 48 cases of Enterobacter-caused bloodstream infection by using in silico DNA-DNA hybridization to identify precise species. Strains belonged to 12 species; Enterobacter xiangfangensis (n = 21) and an unnamed species (taxon 1, n = 8) were dominant. Most (63.5%) Enterobacter strains (n = 349) with genomes in GenBank from human blood are E. xiangfangensis; taxon 1 (19.8%) was next most common. E. xiangfangensis and taxon 1 were associated with increased deaths (20.7% vs. 15.8%), lengthier hospitalizations (median 31 d vs. 19.5 d), and higher resistance to aztreonam, cefepime, ceftriaxone, piperacillin-tazobactam, and tobramycin. Strains belonged to 37 sequence types (STs); ST171 (E. xiangfangensis) was most common (n = 6). Four ST171 strains belonged to a defined clone. Precise species identification has greater implications for epidemiology and infection control than treatment.
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http://dx.doi.org/10.3201/eid2701.190154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774573PMC
January 2021

Mechanical Properties of Additively Manufactured Thermoplastic Polyurethane (TPU) Material Affected by Various Processing Parameters.

Polymers (Basel) 2020 Dec 16;12(12). Epub 2020 Dec 16.

Centre for Innovative Structures and Materials, School of Engineering, RMIT University, Melbourne, VIC 3001, Australia.

Thermoplastic polyurethane (TPU) is a polymer material that has high ductility, good biocompatibility and excellent abrasion resistance. These properties open a pathway to manufacturing functional TPU parts for applications in various fields such as aerospace engineering, medical devices and sports equipment. This study aims to investigate the mechanical properties of additively manufactured TPU material affected by three different processing parameters, including build orientation, mix ratio of the new and reused powders and post-processing. A series of material tests are conducted on TPU dumb-bell specimens. It is found that the mix ratio of the new powder is the most critical factor in improving the mechanical properties of the printed TPU parts. Compared to reused powder, new powder has better particle quality and thermal properties. Besides, build orientation is also a very important factor. TPU parts printed in flat and on-edge orientations show better tensile strength and deformability than those printed in upright orientation. In addition, post-processing is found to significantly enhance the deformability of TPU parts.
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http://dx.doi.org/10.3390/polym12123010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767280PMC
December 2020

Radiosensitization Effect of AGuIX, a Gadolinium-Based Nanoparticle, in Nonsmall Cell Lung Cancer.

ACS Appl Mater Interfaces 2020 Dec 16;12(51):56874-56885. Epub 2020 Dec 16.

Institute Light and Mater, UMR5306, Lyon1 University-CNRS, Lyon University, 69100 Villeurbanne, France.

Radiotherapy is the main treatment for cancer patients. A major concern in radiotherapy is the radiation resistance of some tumors, such as human nonsmall cell lung cancer. However, the radiation dose delivered to the tumors is often limited by the possibility of collateral damage to surrounding healthy tissues. A new and efficient gadolinium-based nanoparticle, AGuIX, has recently been developed for magnetic resonance imaging-guided radiotherapy and has been proven to act as an efficient radiosensitizer. The amplified radiation effects of AGuIX nanoparticles appear to be due to the emission of low-energy photoelectrons and Auger electron interactions. We demonstrated that AGuIX nanoparticles exacerbated radiation-induced DNA double-strand break damage and reduced DNA repair in the H1299 nonsmall cell lung cancer cell line. Furthermore, we observed a significant improvement in tumor cell damage and growth suppression, under radiation therapy, with the AGuIX nanoparticles in a H1299 mouse xenograft model. This study paves the way for research into the radiosensitization mechanism of AGuIX nanoparticles and provides a scientific basis for the use of AGuIX nanoparticles as radiosensitizing drugs.
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http://dx.doi.org/10.1021/acsami.0c16548DOI Listing
December 2020

PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of or .

Front Oncol 2020 26;10:574525. Epub 2020 Nov 26.

Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.

Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting , a well-established driver gene in high-risk neuroblastoma, is still challenging. In recent years, inhibition of bromodomain and extra terminal (BET) proteins shows great potential in multiple of -driven tumors. ARV-825 is a novel BET inhibitor using proteolysis-targeting chimera (PROTAC) technology which degrades target proteins by the proteasome. In this study, we investigated the effect of ARV-825 in neuroblastoma and . Our results showed that ARV-825 treatment robustly induced proliferative suppression, cell cycle arrest, and apoptosis in NB cells. Moreover, ARV-825 efficiently depleted BET protein expression, subsequently repressing the expression of or . In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve / manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.
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http://dx.doi.org/10.3389/fonc.2020.574525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726414PMC
November 2020