Publications by authors named "Jiang Liu"

873 Publications

Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity.

J Med Chem 2021 Oct 14. Epub 2021 Oct 14.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that , as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01451DOI Listing
October 2021

Proxy-bridged Image Reconstruction Network for Anomaly Detection in Medical Images.

IEEE Trans Med Imaging 2021 Oct 13;PP. Epub 2021 Oct 13.

Anomaly detection in medical images refers to the identification of abnormal images with only normal images in the training set. Most existing methods solve this problem with a self-reconstruction framework, which tends to learn an identity mapping and reduces the sensitivity to anomalies. To mitigate this problem, in this paper, we propose a novel Proxy-bridged Image Reconstruction Network (ProxyAno) for anomaly detection in medical images. Specifically, we use an intermediate proxy to bridge the input image and the reconstructed image. We study different proxy types, and we find that the superpixel-image (SI) is the best one. We set all pixels' intensities within each superpixel as their average intensity, and denote this image as SI. The proposed ProxyAno consists of two modules, a Proxy Extraction Module and an Image Reconstruction Module. In the Proxy Extraction Module, a memory is introduced to memorize the feature correspondence for normal image to its corresponding SI, while the memorized correspondence does not apply to the abnormal images, which leads to the information loss for abnormal image and facilitates the anomaly detection. In the Image Reconstruction Module, we map an SI to its reconstructed image. Further, we crop a patch from the image and paste it on the normal SI to mimic the anomalies, and enforce the network to reconstruct the normal image even with the pseudo abnormal SI. In this way, our network enlarges the reconstruction error for anomalies. Extensive experiments on brain MR images, retinal OCT images and retinal fundus images verify the effectiveness of our method for both image-level and pixel-level anomaly detection.
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http://dx.doi.org/10.1109/TMI.2021.3118223DOI Listing
October 2021

Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.

Mol Cancer 2021 Oct 11;20(1):131. Epub 2021 Oct 11.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Shanghai, 200032, China.

Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.
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http://dx.doi.org/10.1186/s12943-021-01428-1DOI Listing
October 2021

The underappreciated role of natural organic matter bond Hg(II) and nanoparticulate HgS as substrates for methylation in paddy soils across a Hg concentration gradient.

Environ Pollut 2021 Oct 8;292(Pt A):118321. Epub 2021 Oct 8.

State Key Laboratory of Environmental Geochemistry, Institute of Geochemistry, Chinese Academy of Sciences, Guiyang, 550081, China. Electronic address:

Rice consumption is the major pathway for human methylmercury (MeHg) exposure in inland China, especially in mercury (Hg) contaminated regions. MeHg production, a microbially driven process, depends on both the chemical speciation of inorganic divalent mercury, Hg(II), that determines Hg bioavailability for methylation. Studies have shown that Hg(II) speciation in contaminated paddy soils is mostly controlled by natural organic matter and sulfide levels, which are typically thought to limit Hg mobility and bioavailability. Yet, high levels of MeHg are found in rice, calling for reconsideration of the nature of Hg species bioavailable to methylators in paddy soils. Here, we conducted incubation experiments using a multi-isotope tracer technique including Hg(NO), natural organic matter bond Hg(II) (NOM-Hg(II)), ferrous sulfide sorbed Hg(II) (≡FeS-Hg(II)), and nanoparticulate mercuric sulfide (nano-HgS), to investigate the relative importance of geochemically diverse yet relevant Hg(II) species on Hg methylation in paddy soils across a Hg concentration gradient. We show that methylation rates for all Hg(II) species tested decreased with increasing Hg concentrations, and that methylation rates using NOM-Hg(II) and nano-HgS as substrates were similar or greater than rates obtained using the labile Hg(NO) substrate. ≡FeS-Hg(II) yielded the lowest methylation rate in all sites, and thus the formation of FeS is likely a sink for labile Hg(NO) in sulfide-rich paddy soils. Moreover, the variability in the methylation data for a given site (1 to 5-fold variation depending on the Hg species) was smaller than what was observed across the Hg concentration gradient (10-10 fold variation between sites). These findings emphasize that at broad spatial scales, site-specific characteristics, such as microbial community structure, need to be taken into consideration, alongside the nature of the Hg substrate available for methylation, to determine net MeHg production. This study highlights the importance of developing site-specific strategies for remediating Hg pollution.
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http://dx.doi.org/10.1016/j.envpol.2021.118321DOI Listing
October 2021

Superficial Macula Capillary Complexity Changes Are Associated With Disability in Neuromyelitis Optica Spectrum Disorders.

Front Neurol 2021 22;12:724946. Epub 2021 Sep 22.

Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.

We examined the macular microvascular changes of the macula in neuromyelitis optica spectrum disorder (NMOSD) patients and its association with their disability and other clinical variables. Thirty-four NMOSD (13 patients without optic neuritis, NMOSD-NON, and 21 patients with a history of optic neuritis, NMOSD-ON) and 44 healthy controls (HCs) were included in the study. Optical coherence tomographic angiography (OCTA) was used to image the superficial (SCP), deep (DCP), and whole capillary plexus (WCP) in a 2.5-mm-diameter concentric circle [excluding the foveal avascular zone (FAZ)]. An algorithm (D) was used to quantify the complexity of the three capillary layers by fractal analysis. We also evaluated the expanded disability scale status (EDSS). D values were significantly reduced in SCP ( < 0.001), DCP ( < 0.001), and WCP ( = 0.003) of NMOSD when compared with HCs. D values were significantly reduced in NMOSD eyes with optic neuritis when compared with healthy controls ( < 0.001) and eyes without optic neuritis ( = 0.004) in the SCP. In the DCP, eyes with optic neuritis showed significantly reduced D values when compared with eyes without optic neuritis ( = 0.016) and healthy controls ( < 0.001); eyes without optic neuritis showed significantly reduced D values ( = 0.007) in the DCP when compared with healthy controls. A significant negative correlation (Rho = -0.475, = 0.005) was shown between the superficial macula D values and the EDSS in NMOSD patients. Additionally, a negative correlation (Rho = -0.715, = 0.006) was seen in the superficial D values in [e]eyes without optic neuritis and EDSS. Macular microvascular damage in the superficial plexus is associated with disability in NMOSD. Macular microvascular alterations arise independently of the occurrence of ON in NMOSD.
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http://dx.doi.org/10.3389/fneur.2021.724946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492905PMC
September 2021

Outer Retinal Layer Thickness Changes in White Matter Hyperintensity and Parkinson's Disease.

Front Neurosci 2021 14;15:741651. Epub 2021 Sep 14.

Department of Computer Science and Engineering, Southern University of Science and Technology, Shenzhen, China.

To investigate the thickness changes of outer retinal layers in subjects with white matter hyperintensities (WMH) and Parkinson's Disease (PD). 56 eyes from 31 patients with WMH, 11 eyes from 6 PD patients, and 58 eyes from 32 healthy controls (HC) were enrolled in this study. A macular-centered scan was conducted on each participant using a spectral-domain optical coherence tomography (SD-OCT) device. After speckle noise reduction, a state-of-the-art deep learning method (i.e., a context encoder network) was employed to segment the outer retinal layers from OCT -scans. Thickness quantification of the outer retinal layers was conducted on the basis of the segmentation results. WMH patients had significantly thinner Henle fiber layers, outer nuclear layers (HFL+ONL) and photoreceptor outer segments (OS) than HC ( = 0.031, and = 0.005), while PD patients showed a significant increase of mean thickness in the interdigitation zone and the retinal pigment epithelium/Bruch complex (IZ+RPE) (19.619 ± 4.626) compared to HC (17.434 ± 1.664). There were no significant differences in the thickness of the outer plexiform layer (OPL), the myoid and ellipsoid zone (MEZ), and the IZ+RPE layer between WMH and HC subjects. Similarly, there were also no obvious differences in the thickness of the OPL, HFL+ONL, MEZ and the OS layer between PD and HC subjects. Thickness changes in HFL+ONL, OS, and IZ+RPE layers may correlate with brain-related diseases such as WMH and PD. Further longitudinal study is needed to confirm HFL+ONL/OS/IZ+RPE layer thickness as potential biomarkers for detecting certain brain-related diseases.
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http://dx.doi.org/10.3389/fnins.2021.741651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477009PMC
September 2021

Noise reduction by adaptive-SIN filtering for retinal OCT images.

Sci Rep 2021 Sep 30;11(1):19498. Epub 2021 Sep 30.

Department of Computer Science and Engineering, Southern University of Science and Technology, Shenzhen, 518055, China.

Optical coherence tomography (OCT) images is widely used in ophthalmic examination, but their qualities are often affected by noises. Shearlet transform has shown its effectiveness in removing image noises because of its edge-preserving property and directional sensitivity. In the paper, we propose an adaptive denoising algorithm for OCT images. The OCT noise is closer to the Poisson distribution than the Gaussian distribution, and shearlet transform assumes additive white Gaussian noise. We hence propose a square-root transform to redistribute the OCT noise. Different manufacturers and differences between imaging objects may influence the observed noise characteristics, which make predefined thresholding scheme ineffective. We propose an adaptive 3D shearlet image filter with noise-redistribution (adaptive-SIN) scheme for OCT images. The proposed adaptive-SIN is evaluated on three benchmark datasets using quantitative evaluation metrics and subjective visual inspection. Compared with other algorithms, the proposed algorithm better removes noise in OCT images and better preserves image details, significantly outperforming in terms of both quantitative evaluation and visual inspection. The proposed algorithm effectively transforms the Poisson noise to Gaussian noise so that the subsequent shearlet transform could optimally remove the noise. The proposed adaptive thresholding scheme optimally adapts to various noise conditions and hence better remove the noise. The comparison experimental results on three benchmark datasets against 8 compared algorithms demonstrate the effectiveness of the proposed approach in removing OCT noise.
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http://dx.doi.org/10.1038/s41598-021-98832-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484270PMC
September 2021

Conditional control of chimeric antigen receptor T-cell activity through a destabilizing domain switch and its chemical ligand.

Cytotherapy 2021 Sep 28. Epub 2021 Sep 28.

Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China. Electronic address:

Background Aims: Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy, adverse effects, including cytokine release syndrome and neurotoxicity, impede its therapeutic application, thus making the modulation of CAR T-cell activity a priority. The destabilizing domain mutated from Escherichia coli dihydrofolate reductase (DHFR) is inherently unstable and degraded by proteasomes unless it is stabilized by its chemical ligand trimethoprim (TMP), a Food and Drug Administration-approved drug. Here the authors reveal a strategy to modulate CAR T-cell activity at the protein level by employing DHFR and TMP as a chemical switch system.

Methods: First, the system was demonstrated to work in human primary T cells. To introduce the system to CAR T cells, DHFR was genetically fused to the carboxyl terminal of a third-generation CAR molecule targeting CD19 (CD19-CAR), constructing the CD19-CAR-DHFR fusion.

Results: The CD19-CAR-DHFR molecule level was shown to be modulated by TMP. Importantly, the incorporation of DHFR had no impact on the recognition specificity and normal function of the CAR molecule. Little adverse effect on cell proliferation and apoptosis was detected. It was proved that TMP could regulate cytokine secretion and the in vitro cytotoxicity of CD19-CAR-DHFR T cells. Furthermore, the in vivo anti-tumor efficacy was demonstrated to be controllable through the manipulation of TMP administration. The approach to control CD19-CAR also succeeded in 19-BBZ(71), another CD19-targeting CAR with a different structure.

Conclusions: The proposed approach based on DHFR and TMP provides a facile strategy to bring CAR T-cell therapy under conditional user control, and the strategy may have the potential to be transplantable.
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http://dx.doi.org/10.1016/j.jcyt.2021.07.014DOI Listing
September 2021

Predesign of Catalytically Active Sites via Stable Coordination Cluster Model System for Electroreduction of CO2 to Ethylene.

Angew Chem Int Ed Engl 2021 Sep 29. Epub 2021 Sep 29.

Nanjing Normal University, School of Chemistry and Material Science, CHINA.

Purposefully designing the well-defined catalysts for the selective electroreduction of CO2 to C2H4 is an extremely important but challenging work. In this work, three crystalline trinuclear copper clusters (Cu3-X, X= Cl-, Br-, NO3-) have been designed, containing three active Cu sites with the identical coordination environment and appropriate spatial distance, delivering high selectivity for the electrocatalytic reduction of CO2 to C2H4. The highest faradaic efficiency of Cu3-X for CO2-to-C2H4 conversion can be adjusted from 31.90% to 55.01% by simply replacing the counter anions (NO3-, Cl-, Br-). The DFT calculation results verify that Cu3-X can facilitate the C-C coupling of identical *CHO intermediates, subsequently forming molecular symmetrical C2H4 product. This work provides an important molecular model system and a new design perspective for electroreduction of CO2 to C2 products with symmetrical molecular structure.
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http://dx.doi.org/10.1002/anie.202111265DOI Listing
September 2021

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Hepatobiliary Pancreat Dis Int 2021 Sep 8. Epub 2021 Sep 8.

Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.
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http://dx.doi.org/10.1016/j.hbpd.2021.09.001DOI Listing
September 2021

Characterization and Phylogenetic Analysis of the Complete Mitochondrial Genome of Saturnia japonica.

Biochem Genet 2021 Sep 22. Epub 2021 Sep 22.

School of Life Sciences, Anhui Agricultural University, Hefei, 230036, People's Republic of China.

The complete mitochondrial genome (mitogenome) of Saturnia japonica (Lepidoptera: Saturniidae) was sequenced and annotated. It is a circular molecule of 15, 376 bp, composed of 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNA), and an adenine (A) + thymine (T)-rich region. All protein-coding genes (PCGs) are initiated by the ATN codon except for cytochrome c oxidase subunit 1 (cox1) gene that is seemingly initiated by the CGA codon. Except for cox2 and nad4, which were terminated by incomplete stop codon T or TA, the rest were terminated by canonical stop codon TAA. The A + T-rich region is high conservative, including 'ATAGA' motif followed by a 19 bp poly-T stretch, a microsatellite-like element (AT) and also a poly-A element, with a total length of 332 bp. The Asn codon was the most frequently used codon, followed by Ile, Leu2, Lys, Met, Phe, and Tyr, while Cys was the least frequently used codon. Phylogenetic relationships analysis based on the 13 PCGs by using maximum likelihood (ML) and neighbor Joining (NJ) revealed that S. japonica belongs to the Saturniidae family. In this study, the annotation and characteristics of the mitogenome of S. japonica were resolved for the first time, which laid a foundation for species classification and the molecular evolution of Lepidoptera: Saturniidae.
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http://dx.doi.org/10.1007/s10528-021-10129-9DOI Listing
September 2021

Gravity Reduced Nitrogen Uptake the Regulation of Brace Unilateral Root Growth in Maize Intercropping.

Front Plant Sci 2021 6;12:724909. Epub 2021 Sep 6.

College of Agronomy, Sichuan Agricultural University, Chengdu, China.

Water, nutrient, light, and interspecific facilitation regulation of soil physicochemical properties and root morphology modulate nitrogen (N) uptake in cereal and legume intercropping systems. However, maize root morphological plasticity and N uptake capability response to gravity in the intercropping system remains to be determined. In this study, maize was grown under 20 cm (I), 40 cm (I), and 60 cm (I) of narrow row spacing in an intercropping system (maize-soybean strip relay intercropping) and equal row spacing of monoculture (M) in a 2-year field experiment. As a supplementary for the field experiment, maize root barrier and plant inclination experiments were conducted. Plant inclination, brace root morphology, N uptake, indole-3-acetic acid (IAA) level, IAA synthesis genes, and grain yield were assessed. The result showed that the plant inclination increased with decreasing narrow row spacing in intercropping system. Also, the brace unilateral root growth ratio (BURR) increased with increasing plant inclination in intercropping treatments. The plant inclination experiment showed the BURR achieved 94% after inclination at 45°. BURR tended to be positively correlated ( = 0.00) with plant inclination. Thus, gravity (plant inclination) causes brace unilateral root growth. The IAA concentration of stem nodes in the wide row increased with increasing plant inclination, while the IAA accumulation decreased in the narrow row. The and genes (associated with IAA biosynthesis) were highly expressed in a wide row. There was a strong correlation ( = 0.03) between the IAA concentration of wide row and the BURR. Therefore, gravity regulates the IAA level, which affects BURR. In addition, the brace root number, volume, and surface area were decreased when BURR was increased. Subsequently, the leaf N, cob N, and kernel N accumulation were reduced. These organs N and grain yield in I were not significantly different as compared to the control treatment. The excessive brace unilateral root growth was not conducive to N uptake and increased yield. Our results suggest that gravity is essential in regulating root morphology plasticity by regulating IAA levels and decreasing N uptake capacity. Furthermore, these results indicate that plant inclination can regulate root phenotype and N uptake of maize and by adjusting the spacing of narrow maize row, we can improve the N uptake and yield of the maize-soybean strip relay-intercropping system.
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http://dx.doi.org/10.3389/fpls.2021.724909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450519PMC
September 2021

The development and improvement of ribonucleic acid therapy strategies.

Mol Ther Nucleic Acids 2021 Sep 14. Epub 2021 Sep 14.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, 610041, Chengdu, China.

The biological understanding of RNA has evolved since the discovery of catalytic RNAs in the early 1980s and the establishment of RNA interference (RNAi) in the 1990s. RNA is no longer seen as the simple mid-product between transcription and translation, but potential molecules to be developed as RNA therapeutic drugs. RNA-based therapeutic drugs have gained recognition due to their ability to regulate gene expression and perform cellular functions. Various nucleobase, backbone, and sugar-modified oligonucleotides have been synthesized, as natural oligonucleotides with some limitations such as poor low nuclease resistance, binding affinity, poor cellular uptake and toxicity, which affect their use as RNA therapeutic drugs. In this review, we briefly discuss different RNA therapeutic drugs and the internal connection, including antisense oligonucleotides, siRNA and miRNA, aptamers, saRNA, and RNA vaccines, we also discuss the important roles of RNA vaccines and their use in the fight against COVID-19. In addition, various chemical modifications and delivery systems used to improve the performance of RNA therapeutic drugs and overcome their limitations are discussed.
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http://dx.doi.org/10.1016/j.omtn.2021.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437697PMC
September 2021

Plasmacytoid dendritic cells recruited by HIF-1α/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma.

Cancer Lett 2021 Dec 16;522:80-92. Epub 2021 Sep 16.

Department of Surgery, Faculty of Medicine and HKU-SZH, The University of Hong Kong, Hong Kong, China. Electronic address:

Plasmacytoid dendritic cells (pDCs) play immunosuppressive roles in the tumor microenvironment (TME). However, the molecular mechanisms underlying the recruitment and dysfunction of pDCs in the TME remain largely elusive, especially in hepatocellular carcinoma (HCC). In this study, we observed the accumulation of pDCs in the blood, tumor tissue, and ascitic fluid of HCC patients. A high density of tumor-infiltrating pDCs was correlated with poor prognosis in patients with HCC. Hypoxia-induced extracellular adenosine (eADO) significantly enhanced pDC recruitment into tumors via the adenosine A1 receptor (ADORA1). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transcriptionally upregulated the expression of the ectonucleotidases CD39 and CD73 in HCC cells, both of which are essential for the generation of eADO. Moreover, eADO-stimulated pDCs promoted the induction of regulatory T cells and suppressed proliferation and cytotoxicity of CD8 T cells. Depletion of pDCs using a monoclonal antibody or an ADORA1 antagonist significantly improved antitumor immunity and suppressed HCC growth in the immunocompetent HCC mouse model. Thus, targeting pDC recruitment may serve as a potential adjuvant strategy for immunotherapies in HCC.
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http://dx.doi.org/10.1016/j.canlet.2021.09.022DOI Listing
December 2021

Integrated mobile container PCR laboratory (IMCPL): A novel strategy to reduce unnecessary rapid antigen testing.

J Infect 2021 Sep 16. Epub 2021 Sep 16.

Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250012, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2021.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443311PMC
September 2021

Versatile TiCT MXene for free-radical scavenging.

Nano Res 2021 Sep 9:1-9. Epub 2021 Sep 9.

Flexible Printed Electronics Technology Center and School of Science, Harbin Institute of Technology (Shenzhen), Shenzhen, 518055 China.

MXene, as an emerging two-dimensional (2D) material with ultrathin structure and fascinating physiochemical properties, has been widely explored in broad applications. Versatile functions of MXenes are continuously explored. This work presents distinctive feature of MXene-TiCT nanosheets for free-radical (FRs) scavenging that never reported before. We demonstrated the mechanism and equation in regard to the reaction between TiCT and HO, which was applied to design colorimetric HO strip assay with good performance. The good FRs scavenging capability of TiCT , including a series of reactive oxygen species (ROS) and reactive nitrogen species (RNS), was systemically confirmed. The antioxidation capability of TiCT for protecting cells from oxidative damage was demonstrated using the oxidative damage model of alpha mouse liver 12 (AML-12) cells. This original work provides huge opportunities for MXenes in FR-related biomedical applications.

Electronic Supplementary Material: Supplementary material (further details of the experimental procedures, investigation of the reaction between TiCT and other oxidants, the characterization of endocytosis of cells for TiCT , and the comparison of different antioxidants for scavenging free radicals) is available in the online version of this article at 10.1007/s12274-021-3751-y.
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http://dx.doi.org/10.1007/s12274-021-3751-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427154PMC
September 2021

Hybrid Variation-aware Network for Angle-closure Assessment in AS-OCT.

IEEE Trans Med Imaging 2021 Sep 6;PP. Epub 2021 Sep 6.

Automatic angle-closure assessment in Anterior Segment OCT (AS-OCT) images is an important task for the screening and diagnosis of glaucoma, and the most recent computer-aided models focus on a binary classification of anterior chamber angles (ACA) in AS-OCT, i.e., open-angle and angle-closure. In order to assist clinicians who seek better to understand the development of the spectrum of glaucoma types, a more discriminating three-class classification scheme was suggested, i.e., the classification of ACA was expended to include open-, appositional- and synechial angles. However, appositional and synechial angles display similar appearances in an AS-OCT image, which makes classification models struggle to differentiate angle-closure subtypes based on static AS-OCT images. In order to tackle this issue, we propose a 2D-3D Hybrid Variation-aware Network (HV-Net) for open-appositional-synechial ACA classification from AS-OCT imagery. Specifically, taking into account clinical priors, we first reconstruct the 3D iris surface from an AS-OCT sequence, and obtain the geometrical characteristics necessary to provide global shape information. 2D AS-OCT slices and 3D iris representations are then fed into our HV-Net to extract cross-sectional appearance features and iris morphological features, respectively. To achieve similar results to those of dynamic gonioscopy examination, which is the current gold standard for diagnostic angle assessment, the paired AS-OCT images acquired in dark and light illumination conditions are used to obtain an accurate characterization of configurational changes in ACAs and iris shapes, using a Variation-aware Block. In addition, an annealing loss function was introduced to optimize our model, so as to encourage the sub-networks to map the inputs into the more conducive spaces to extract dark-to-light variation representations, while retaining the discriminative power of the learned features. The proposed model is evaluated across 1584 paired AS-OCT samples, and it has demonstrated its superiority in classifying open-, appositional- and synechial angles.
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http://dx.doi.org/10.1109/TMI.2021.3110602DOI Listing
September 2021

Unravelling the interactive effect of soil and atmospheric mercury influencing mercury distribution and accumulation in the soil-rice system.

Sci Total Environ 2021 Aug 28;803:149967. Epub 2021 Aug 28.

State Key Laboratory of Environmental Geochemistry, Institute of Geochemistry, Chinese Academy of Sciences, Guiyang 550002, PR China; Center for Excellence in Quaternary Science and Global Change, Chinese Academy of Sciences, Xian 710061, PR China. Electronic address:

Mercury (Hg) accumulation in rice is an emerging health concern worldwide. However, sources and interactions responsible for Hg species accumulation in different rice tissues are still uncertain. Four experimental plots were carefully designed at an artisanal Hg mining site and a control site to evaluate the effect of atmospheric and soil Hg contents on Hg accumulation in rice. We showed that inorganic Hg (IHg) contents in rice tissues grown either in contaminated or control site soil (non-contaminated soil) were higher at Hg artisanal mining site than those at the control site. Elevated total gaseous mercury (TGM) levels in ambient air were the predominant source of IHg to rice at the Hg mining area. Methylmercury (MeHg) concentrations in rice plant tissues increased in proportionality with MeHg contents in paddy soil. Our results suggest that both atmosphere and soil Hg sources have been impacted the IHg accumulation in rice. Above ground rice tissues, grains, leaves, and stalk accumulated IHg from both atmosphere and soil to varying degrees. Nonetheless, the study also provides the first direct evidence that atmospheric Hg accumulated by above-ground rice tissues could be translocated to below-ground tissues (roots). However, the extent to which atmosphere or soil Hg contributes to IHg in rice tissues may vary with each source's concentration gradient at the given site. No evidence of in planta Hg methylation was found during the current study. Hence, paddy fields are potential MeHg production sites, whereas paddy soil is a unique MeHg accumulation source in rice plants. This study expands and clarifies the contribution of various sources involved in Hg accumulation in the soil rice system. The findings here provide the basis for future research strategies to deal with the global issue of Hg contaminated rice.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149967DOI Listing
August 2021

Design of Crystalline Reduction-Oxidation Cluster-Based Catalysts for Artificial Photosynthesis.

JACS Au 2021 Aug 8;1(8):1288-1295. Epub 2021 Jul 8.

School of Chemistry, South China Normal University, Guangzhou 510006, P. R. China.

Metal cluster-based compounds have difficulty finishing the photocatalytic carbon dioxide reduction reaction (CORR) and water oxidation reaction (WOR) simultaneously because of the big challenge in realizing the coexistence of independently and synergistically reductive and oxidative active sites in one compound. Herein, we elaborately designed and synthesized one kind of crystalline reduction-oxidation () cluster-based catalysts connecting reductive { } (M = Zn, Co, and Ni for , , respectively) cluster and oxidative {PMoVO} cluster through a single oxygen atom bridge to achieve artificial photosynthesis successfully. These clusters can all photocatalyze CO-to-CO and HO-to-O reactions simultaneously, of which the CO yield of is 13.8 μmol/g·h, and the selectivity is nearly 100%. Density functional theory calculations reveal that the concomitantly catalytically reductive and oxidative active sites (for CORR and WOR, respectively) and the effective electron transfer between the sites in these photocatalysts are the key factors to complete the overall photosynthesis.
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http://dx.doi.org/10.1021/jacsau.1c00186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397352PMC
August 2021

biocompatibility and degradability of a Zn-Mg-Fe alloy osteosynthesis system.

Bioact Mater 2022 Jan 30;7:154-166. Epub 2021 May 30.

State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, 145 West Changle Road, Xi'an, 710032, PR China.

Zinc is generally considered to be one of the most promising materials to be used in biodegradable implants, and many zinc alloys have been optimized to improve implant biocompatibility, degradation, and mechanical properties. However, long-term degradation leads to the prolonged presence of degradation products, which risks foreign body reactions. Herein, we investigated the biocompatibility and degradation of a biodegradable Zn-Mg-Fe alloy osteosynthesis system in the frontal bone, mandible, and femur in beagles for 1 year. Results of the routine blood, biochemical, trace element, and histological analyses of multiple organs, peripheral blood CD4/CD8a levels, and serum interleukin 2 and 4 levels showed good biocompatibility of the Zn-Mg-Fe alloy. Zinc content analysis revealed zinc accumulation in adjacent bone tissue, but not in the liver, kidney, and spleen, which was related to the degradation of the Zn-Mg-Fe alloy. The alloy demonstrated a uniform slowing degradation rate . No degradation differences in the frontal bone, mandible, and femur were observed. The degradation products included zinc oxide [ZnO], zinc hydroxide [Zn(OH)], hydrozincite [Zn(OH)(CO)], and hopeite [Zn(PO)·4HO]. The good biocompatibility and degradation properties of the Zn-Mg-Fe alloy render it a very attractive osteosynthesis system for clinical applications.
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http://dx.doi.org/10.1016/j.bioactmat.2021.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379423PMC
January 2022

FDA Approval Summary: Nivolumab in Combination with Ipilimumab for the Treatment of Unresectable Malignant Pleural Mesothelioma.

Clin Cancer Res 2021 Aug 30. Epub 2021 Aug 30.

Center for Drug Evaluation and Research and Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland.

On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years ( = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed ( = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8-21.5] compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89; = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1466DOI Listing
August 2021

Geospace Plume and Its Impact on Dayside Magnetopause Reconnection Rate.

J Geophys Res Space Phys 2021 Jun 21;126(6):e2021JA029117. Epub 2021 Jun 21.

Los Alamos National Laboratory Los Alamos NM USA.

The role a geospace plume in influencing the efficiency of magnetopause reconnection is an open question with two contrasting theories being debated. A local-control theory suggests that a plume decreases both local and global reconnection rates, whereas a global-control theory argues that the global reconnection rate is controlled by the solar wind rather than local physics. Observationally, limited numbers of point measurements from spacecraft cannot reveal whether a local change affects the global reconnection. A distributed observatory is hence needed to assess the validity of the two theories. We use THEMIS and Los Alamos National Laboratory spacecraft to identify the occurrence of a geospace plume and its contact with the magnetopause. Global evolution and morphology of the plume is traced using GPS measurements. SuperDARN is then used to monitor the distribution and the strength of dayside reconnection. Two storm-time geospace plume events are examined and show that as the plume contacts the magnetopause, the efficiency of reconnection decreases at the contact longitude. The amount of local decrease is 81% and 68% for the two events, and both values are consistent with the mass loading effect of the plume if the plume's atomic mass is ∼4 amu. Reconnection in the surrounding is enhanced, and when the solar wind driving is stable, little variation is seen in the cross polar cap potential. This study illuminates a pathway to resolve the role of cold dense plasma on solar wind-magnetosphere coupling, and the observations suggest that plumes redistribute magnetopause reconnection activity without changing the global strength substantially.
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http://dx.doi.org/10.1029/2021JA029117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365764PMC
June 2021

Synthesis of Isothiazoles through -Propargylsulfinylamide: TFA-Promoted Sulfinyl Group-Involved Intramolecular Cyclization.

Org Lett 2021 Sep 23;23(17):6941-6945. Epub 2021 Aug 23.

Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, International Innovation Center for Forest Chemicals and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China.

A new reactivity mode of -butanesulfinamide has been developed, which proceeds through C-S and O-S bond cleavage of -propargyl -butanesulfinylamide allowing rapid assembly of poly functionalized isothiazoles. This intramolecular cyclization reaction could be conducted under mild and convenient conditions and tolerates several fluoroalkyl and substituted phenyl groups with good chemical yields. This reaction not only represents a new reactivity of -butanesulfinamide but also provides an easy strategy for the synthesis of isothiazoles.
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http://dx.doi.org/10.1021/acs.orglett.1c02538DOI Listing
September 2021

Circular RNA CircEYA3 induces energy production to promote pancreatic ductal adenocarcinoma progression through the miR-1294/c-Myc axis.

Mol Cancer 2021 08 21;20(1):106. Epub 2021 Aug 21.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, PR China.

Background: Extensive studies have demonstrated the pivotal roles of circular RNAs (circRNAs) in the occurrence and development of different human cancers. However, the expression and regulatory roles of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear.

Methods: CircEYA3 was explored based on Gene Expression Omnibus (GEO) dataset analysis. qRT-PCR was applied to determine the expression of circRNAs, miRNAs and mRNAs in PDAC cells and tissues. The biological roles of circEYA3 in vitro and in vivo were determined by performing a series of functional experiments. Further, dual luciferase reporter, fluorescence in situ hybridization (FISH), RNA pull-down assays, and RNA immunoprecipitation (RIP) assays were used to confirm the interaction of circEYA3 with miR-1294.

Results: CircEYA3 was elevated in PDAC tissues and cells, and a higher level of circEYA3 was significantly associated with a poorer prognosis in patients with PDAC. Functionally, circEYA3 increased energy production via ATP synthesis to promote PDAC progression in vitro and in vivo. Mechanistically, circEYA3 functions as an endogenous miR-1294 sponge to elevate c-Myc expression, thus exerting its oncogenic functions.

Conclusion: CircEYA3 promotes the progression of PDAC through the miR-1294/c-Myc signalling axis, and circEYA3 may be an efficient molecular therapeutic target in PDAC.
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http://dx.doi.org/10.1186/s12943-021-01400-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379744PMC
August 2021

Design, structure-activity relationship study and biological evaluation of the thieno[3,2-c]isoquinoline scaffold as a potential anti-cancer agent.

Bioorg Med Chem Lett 2021 Aug 18;52:128327. Epub 2021 Aug 18.

Department of Chemistry & Biochemistry, Concordia University, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6, Canada; Center for Green Chemistry and Catalysis, Department of Chemistry, McGill University, 801 rue Sherbrooke O., Montréal, QC H3A 0B8, Canada. Electronic address:

Several derivatives of a series that share a thienoisoquinoline scaffold have demonstrated potent activity against cancer cell lines A549, HeLa, HCT-116, and MDA-MB-231 in the submicromolar concentration range. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. A series of compounds have been identified as the most promising with submicromolar IC values against a lung cancer cell line (A549). Microscopy studies of cancer cells treated with the lead compound revealed that it causes mitotic arrest and disrupts microtubules. Further evaluation via an in vitro microtubule polymerization assay and competition studies indicate that the lead compound binds to tubulin via the colchicine site.
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http://dx.doi.org/10.1016/j.bmcl.2021.128327DOI Listing
August 2021

A well-defined dual Mn-site based metal-organic framework to promote CO reduction/evolution in Li-CO batteries.

Chem Commun (Camb) 2021 Aug 16. Epub 2021 Aug 16.

Jiangsu Collaborative Innovation Centre of Biomedical Functional Materials, Jiangsu Key Laboratory of New Power Batteries, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, P. R. China. and School of Chemistry, South China Normal University, Guangzhou, 510006, P. R. China.

A series of Li-CO2 battery cathode materials are reported based on metal-organic frameworks with dual-metal sites containing a metalloporphyrin and a metal-coordinated pyrazole. MnTPzP-Mn demonstrates a low voltage hysteresis of 1.05 V at 100 mA g-1 and good stability of 90 cycles at 200 mA g-1. Among them, the Mn-coordinated pyrazole site can promote the effective decomposition of Li2CO3, and the Mn-metalloporphyrin site contributes to the activation of CO2. This is the first example of using a crystalline cathode material with a well-defined structure to reveal natural catalytic sites for CO2 reduction/evolution reactions under aprotic conditions in Li-CO2 batteries.
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http://dx.doi.org/10.1039/d1cc03431fDOI Listing
August 2021

Memorizing Structure-Texture Correspondence for Image Anomaly Detection.

IEEE Trans Neural Netw Learn Syst 2021 Aug 13;PP. Epub 2021 Aug 13.

This work focuses on image anomaly detection by leveraging only normal images in the training phase. Most previous methods tackle anomaly detection by reconstructing the input images with an autoencoder (AE)-based model, and an underlying assumption is that the reconstruction errors for the normal images are small, and those for the abnormal images are large. However, these AE-based methods, sometimes, even reconstruct the anomalies well; consequently, they are less sensitive to anomalies. To conquer this issue, we propose to reconstruct the image by leveraging the structure-texture correspondence. Specifically, we observe that, usually, for normal images, the texture can be inferred from its corresponding structure (e.g., the blood vessels in the fundus image and the structured anatomy in optical coherence tomography image), while it is hard to infer the texture from a destroyed structure for the abnormal images. Therefore, a structure-texture correspondence memory (STCM) module is proposed to reconstruct image texture from its structure, where a memory mechanism is used to characterize the mapping from the normal structure to its corresponding normal texture. As the correspondence between destroyed structure and texture cannot be characterized by the memory, the abnormal images would have a larger reconstruction error, facilitating anomaly detection. In this work, we utilize two kinds of complementary structures (i.e., the semantic structure with human-labeled category information and the low-level structure with abundant details), which are extracted by two structure extractors. The reconstructions from the two kinds of structures are fused together by a learned attention weight to get the final reconstructed image. We further feed the reconstructed image into the two aforementioned structure extractors to extract structures. On the one hand, constraining the consistency between the structures extracted from the original input and that from the reconstructed image would regularize the network training; on the other hand, the error between the structures extracted from the original input and that from the reconstructed image can also be used as a supplement measurement to identify the anomaly. Extensive experiments validate the effectiveness of our method for image anomaly detection on both industrial inspection images and medical images.
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http://dx.doi.org/10.1109/TNNLS.2021.3101403DOI Listing
August 2021

Esophagogastric junction contractile integral abnormalities in patients with proton pump inhibitor-refractory symptoms.

J Dig Dis 2021 Sep 2;22(9):529-535. Epub 2021 Sep 2.

Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.

Objectives: Esophagogastric junction contractile integral (EGJ-CI) is a novel indicator to evaluate quantitatively the esophagogastric junction (EGJ) barrier function. We aimed to assess the role of EGJ-CI in patients with refractory gastroesophageal reflux disease (GERD) symptoms and the correlation between EGJ-CI and impedance-pH monitoring characteristics.

Methods: In total 82 patients with proton pump inhibitors (PPIs)-refractory gastroesophageal reflux symptoms (heartburn or regurgitation) were enrolled. These patients were further divided into two groups based on their EGJ-CI value (39 mmHg·cm). The mean nocturnal baseline impedance (MNBI) was measured to explore its association with EGJ-CI.

Results: The median EGJ-CI in patients with PPI-refractory symptoms was 30.8 mmHg·cm. EGJ-CI was inversely correlated with acid exposure time and reflux episodes; while it was positively correlated with MNBI, distal contractile integral, lower esophageal sphincter basal pressure and integrated relaxation pressure. Patients were further divided into the high (n = 27) and low (n = 55) EGJ-CI groups using a cut-off value of 39.0 mmHg·cm. Patients with a low EGJ-CI had a lower MNBI level than those with a high EGJ-CI (2703 Ω vs 3545 Ω, P = 0.034).

Conclusions: In patients with PPIs-refractory symptoms, EGJ-CI is associated with acid exposure and conventional high-resolution manometry parameters. EGJ-CI may play an important role in the diagnosis and treatment of patients with refractory GERD.
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http://dx.doi.org/10.1111/1751-2980.13038DOI Listing
September 2021

Estimation of the biogeochemical reactivities of dissolved organic matter from modified biochars using color.

Sci Total Environ 2021 Oct 25;790:147974. Epub 2021 May 25.

State Cultivation Base of Eco-Agriculture for Southwest Mountainous Land, Department of Environmental Sciences and Engineering, College of Resources and Environment, Southwest University, Chongqing 400716, China. Electronic address:

Modified biochar is widely used as a soil amendment in agricultural systems to improve crop yields and remove environmental pollutants. The water-soluble fraction of biochar, called biochar-derived dissolved organic matter (DOM), is the most active biochar component. However, the correlation between the optical properties of DOM and its biogeochemical activity remain unclear. In this study, one biochar and six modified derivatives were used to extract DOM and characterize its optical properties. The biogeochemical reactivities of DOM were determined using biodegradation, photodegradation, and electron-donating capacity assays. The results show that modification changes the biochar characteristics, leading to a variety of DOM properties. The DOM from modified biochars degrades more rapidly than the original biochar. On the other hand, modification reduces the redox functional groups in DOM, resulting in a lower electron-donating capacity of DOM samples. However, the modifications did not seem to affect photodegradation. Not all spectral parameters provide information about the correlations between the DOM properties and biogeochemical reactivity. However, two fundamental properties, that is, the specific UV absorbance at 254 nm (SUVA, showing aromaticity) and spectral slopes over the ranges of 275-295 nm of the UV absorbance (S, showing molecular weight), are the dominant factors affecting the biodegradation and electron-donating capacities of DOM. In this study, a rapid and straightforward method is presented, which can be used to characterize DOM and predict the reactivity of biochar that is used as an environmental amendment to minimize toxic organic compounds.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147974DOI Listing
October 2021

Analysis of Immune-Related Signatures Related to CD4+ T Cell Infiltration With Gene Co-Expression Network in Pancreatic Adenocarcinoma.

Front Oncol 2021 23;11:674897. Epub 2021 Jul 23.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid malignancies. Immunotherapy and targeted therapy confirmed an existing certain curative effect in treating PDAC. The aim of this study was to develop an immune-related molecular marker to enhance the ability to predict Stages III and IV PDAC patients.

Method: In this study, weighted gene co-expression network (WGCNA) analysis and a deconvolution algorithm (CIBERSORT) that evaluated the cellular constituent of immune cells were used to evaluate PDAC expression data from the GEO (Gene Expression Omnibus) datasets, and identify modules related to CD4+ T cells. LASSO Cox regression analysis and Kaplan-Meier curve were applied to select and build prognostic multi-gene signature in TCGA Stages III and IV PDAC patients (N = 126). This was followed by independent Stages III and IV validation of the gene signature in the International Cancer Genome Consortium (ICGC, N = 62) and the Fudan University Shanghai Cancer Center (FUSCC, N = 42) cohort. Inherited germline mutations and tumor immunity exploration were applied to elucidate the molecular mechanisms in PDAC. Univariate and Multivariate Cox regression analyses were applied to verify the independent prognostic factors. Finally, a prognostic nomogram was created according to the TCGA-PDAC dataset.

Results: A four-gene signature comprising NAPSB, ZNF831, CXCL9 and PYHIN1 was established to predict overall survival of PDAC. This signature also robustly predicted survival in two independent validation cohorts. The four-gene signature could divide patients into high and low-risk groups with disparity overall survival verified by a Log-rank test. Expression of four genes positively correlated with immunosuppression activity (PD-L1 and PD1). Immune-related genes nomogram and corresponding calibration curves showed significant performance for predicting 3-year survival in TCGA-PDAC dataset.

Conclusion: We constructed a novel four-gene signature to predict the prognosis of Stages III and IV PDAC patients by applying WGCNA and CIBERSORT algorithm scoring to transcriptome data different from traditional methods of filtrating for differential genes in cancer and healthy tissues. The findings may provide reference to predict survival and was beneficial to individualized management for advanced PDAC patients.
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http://dx.doi.org/10.3389/fonc.2021.674897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343184PMC
July 2021
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