Publications by authors named "Bei Zhang"

846 Publications

The Role of GILZ in Lipid Metabolism and Adipocyte Biology.

Prostaglandins Other Lipid Mediat 2022 Aug 4:106668. Epub 2022 Aug 4.

School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, P. R. China. Electronic address:

Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-responsive protein and is thought to mediate part of the anti-inflammatory effects of glucocorticoid receptors (GRs). Its role in inflammation and immune responses has been widely studied since its discovery in 1997. Recently, increasing studies showed that GILZ might be involved in the differentiation of preadipocytes and adipogenesis. This review aims to provide readers with the latest updates on the biology of GILZ. The role and regulatory mechanism of GILZ in lipid metabolism and preadipocytes differentiation were summarized. In addition, new insights on the regulatory mechanism of GILZ in adipocyte browning was also discussed, which proposes a novel therapeutic target for lipid metabolic disorders in the future. However, research related to the function and regulatory mechanisms of GILZ in lipid metabolism and adipocyte biology is still in its infancy, and there is still much work needs to be done.
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http://dx.doi.org/10.1016/j.prostaglandins.2022.106668DOI Listing
August 2022

Near-real-time MODIS-derived vegetation index data products and online services for CONUS based on NASA LANCE.

Sci Data 2022 08 4;9(1):477. Epub 2022 Aug 4.

Center for Spatial Information Science and Systems, George Mason University, Fairfax, VA, 22030, USA.

This paper describes a set of Near-Real-Time (NRT) Vegetation Index (VI) data products for the Conterminous United States (CONUS) based on Moderate Resolution Imaging Spectroradiometer (MODIS) data from Land, Atmosphere Near-real-time Capability for EOS (LANCE), an openly accessible NASA NRT Earth observation data repository. The data set offers a variety of commonly used VIs, including Normalized Difference Vegetation Index (NDVI), Vegetation Condition Index (VCI), Mean-referenced Vegetation Condition Index (MVCI), Ratio to Median Vegetation Condition Index (RMVCI), and Ratio to previous-year Vegetation Condition Index (RVCI). LANCE enables the NRT monitoring of U.S. cropland vegetation conditions within 24 hours of observation. With more than 20 years of observations, this continuous data set enables geospatial time series analysis and change detection in many research fields such as agricultural monitoring, natural resource conservation, environmental modeling, and Earth system science. The complete set of VI data products described in the paper is openly distributed via Web Map Service (WMS) and Web Coverage Service (WCS) as well as the VegScape web application ( https://nassgeodata.gmu.edu/VegScape/ ).
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http://dx.doi.org/10.1038/s41597-022-01565-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352751PMC
August 2022

Glaucocalyxin A Inhibits the Malignant Progression of Epithelial Ovarian Cancer by Affecting the MicroRNA-374b-5p/HMGB3/Wnt-β-Catenin Pathway Axis.

Front Oncol 2022 14;12:955830. Epub 2022 Jul 14.

Department of Gynecology and Obstetrics, Xuzhou Central Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, China.

Objective: Glaucocalyxin A (GLA) is an ent-kaurene diterpenoid from var possessing anti-tumor activity. This study aimed to investigate effects of GLA on epithelial ovarian cancer (EOC) and elucidate underlying mechanisms.

Methods: The expression of HMGB3 in EOC tissues was analyzed by GEPIA and immunohistochemistry. Cell proliferation was determined using CCK-8 and colony formation assays. Cell invasion, migration, and apoptosis were detected using Transwell, wound healing, and flow cytometry assays, respectively. Interactions between HMGB3 and miRNAs were predicted using ENCORI and validated using a dual-luciferase assay. mRNA expression levels of HMGB3 and miRNAs were measured using qPCR. Protein expression levels of HMGB3, E-cadherin, N-cadherin, Wnt3a,β-catenin, Bcl-2, and Bax were measured by western blotting. A tumor xenograft model was established to validate the efficacy and mechanism of GLA .

Results: HMGB3 was upregulated in EOC tissues and cells. GLA dose-dependently inhibited EOC cell proliferation and epithelial-mesenchymal transition (EMT). HMGB3 overexpression promoted proliferation, invasion, migration, and EMT, and suppressed the apoptosis of EOC cells. In addition, miR-374b-5p was targeted by HMGB3, and its overexpression hindered malignant characteristics of EOC cells. HMGB3 overexpression weakened antitumor effects of GLA and miR-374b-5p in EOC cells. Moreover, the Wnt-β-catenin pathway was inhibited by the GLA-mediated miR-374b-5p/HMGB3 axis. experiments showed that GLA inhibited EOC tumor growth, meanwhile, upregulated the miR-374b-5p level and downregulated the expression of HMGB3, Wnt3a, and β-catenin in tumor tissues.

Conclusions: GLA suppressed the malignant progression of EOC by regulating the miR-374b-5p/HMGB3/Wnt-β-catenin pathway axis.
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http://dx.doi.org/10.3389/fonc.2022.955830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329791PMC
July 2022

Orbitofrontal Cortex Functional Connectivity-Based Classification for Chronic Insomnia Disorder Patients With Depression Symptoms.

Front Psychiatry 2022 6;13:907978. Epub 2022 Jul 6.

Department of Neurology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China.

Depression is a common comorbid symptom in patients with chronic insomnia disorder (CID). Previous neuroimaging studies found that the orbital frontal cortex (OFC) might be the core brain region linking insomnia and depression. Here, we used a machine learning approach to differentiate CID patients with depressive symptoms from CID patients without depressive symptoms based on OFC functional connectivity. Seventy patients with CID were recruited and subdivided into CID with high depressive symptom (CID-HD) and low depressive symptom (CID-LD) groups. The OFC functional connectivity (FC) network was constructed using the altered structure of the OFC region as a seed. A linear kernel SVM-based machine learning approach was carried out to classify the CID-HD and CID-LD groups based on OFC FC features. The predict model was further verified in a new cohort of CID group ( = 68). The classification model based on the OFC FC pattern showed a total accuracy of 76.92% ( = 0.0009). The area under the receiver operating characteristic curve of the classification model was 0.84. The OFC functional connectivity with reward network, salience network and default mode network contributed the highest weights to the prediction model. These results were further validated in an independent CID group with high and low depressive symptom (accuracy = 67.9%). These findings provide a potential biomarker for early diagnosis and intervention in CID patients comorbid with depression based on an OFC FC-based machine learning approach.
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http://dx.doi.org/10.3389/fpsyt.2022.907978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299364PMC
July 2022

Effects of dissolved organic matter on the adsorption of norfloxacin on a sandy soil (fraction) from the Yellow River of Northern China.

Sci Total Environ 2022 Jul 20;848:157495. Epub 2022 Jul 20.

Stockbridge School of Agriculture, University of Massachusetts, Amherst, MA 01003, United States.

Dissolved organic matter (DOM), which exists widely in the environment, coming from different sources, may greatly affect the adsorption of antibiotics. However, the adsorption mechanisms of antibiotics in a sandy soil and the effects of DOM from different sources on the adsorption remain poorly understood. This study systematically investigated the adsorption characteristics of norfloxacin (NOR) onto a sandy soil obtained from the banks of Xi'an in Yellow River and in the presence of three DOM including HDOM (commercially available humic acids), LDOM (derived from fallen leaves) and MDOM (derived from cattle manure). Elemental analysis, UV-vis spectroscopy, 3D-EEM, XPS, TOC, SEM, and FTIR were used to analyze the adsorption mechanism. It was found that all the DOM sources we used could reduce the adsorption of NOR on sandy soil and prolong the reaction time to reach adsorption equilibrium. The decreasing adsorption capacities of NOR by the three types of DOM (10 mg/L) followed the order as: HDOM < LDOM < MDOM, which was related to their aromaticity, polarity and hydrophobicity. These adsorption processes of NOR on sandy soil in the presence of DOM were well fitted by Double-chamber first-order kinetics, Linear model and Freundlich models. Besides, the adsorption reaction was endothermic and spontaneous. Adsorption competition of DOM molecules with NOR, or formation of DOM-NOR complexes in solution resulted in a decrease of sandy soil adsorption capacity. Correspondingly, co-adsorption and cumulative adsorption were also considered to be the key processes that determined NOR adsorption towards sandy soil after adding DOM. Moreover, the adsorption of NOR onto sandy soil exhibited strong pH-dependent characteristic and NOR might be more easily leached from sandy soil in the aquifer at an alkaline pH. High-ion strength suppressed the adsorption. These results would help to understand the fate and risk of NOR under the action of different DOM.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157495DOI Listing
July 2022

Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer.

Clin Transl Med 2022 Jul;12(7):e989

Department of VIP Region, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Cancer-associated fibroblasts (CAFs) contributes to overall tumor progression. In the current survey, we explored the ability of microRNA-20a (miR-20a) within these CAF-derived exosomes to influence non-small-cell lung cancer (NSCLC) progression.

Materials And Methods: Normal tissue-associated fibroblasts (NAFs) and CAFs were collected from samples of NSCLC patient tumors and paracancerous lung tissues. Exosomes derived from these cells were then characterized via Western blotting, nanoparticle tracking analyses, and transmission electron microscopy. The expression of miR-20a was assessed via qPCR and fluorescence in situ hybridization (FISH). CCK-8, EdU uptake, and colony formation assessments were used for evaluating tumor proliferation, while Hoechst staining was performed to monitor the in vitro apoptotic death of tumor cells. A model of xenograft tumor established in nude mice was also used to evaluate in vivo tumor responses.

Results: CAF-derived exosomes exhibited miR-20a upregulation and promoted NSCLC cell proliferation and resistance to cisplatin (DDP). Mechanistically, CAF-derived exosomes were discovered to transmit miR-20a to tumor cells wherein it was able to target PTEN to enhance DDP resistance and proliferation. Associated PTEN downregulation following exosome-derived miR-20a treatment enhanced PI3K/AKT pathway activation.

Conclusion: The achieved outcomes explain that CAFs can release miR-20a-containing exosomes capable of promoting NSCLC progression and chemoresistance, highlighting this pathway as a possible therapeutic target in NSCLC.
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http://dx.doi.org/10.1002/ctm2.989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299573PMC
July 2022

Narrow-band RbKNa(LiSiO):Eu(0 ≤ ≤ 1) cyan-blue phosphors for full-spectrum white LEDs.

Dalton Trans 2022 Aug 9;51(31):11703-11712. Epub 2022 Aug 9.

College of Optical and Electronic Technology, China Jiliang University, Hangzhou 310018, China.

A series of RbKNa(LiSiO):Eu(0 ≤ ≤ 1) phosphors were successfully synthesized through a high-temperature solid-state reaction. The introduction of K into the RbNa(LiSiO):Eu phosphor to partially or completely replace Rb allows the emission spectrum to be modulated from blue ( = 473 nm, FWHM = 22.5 nm) to a narrow cyan band ( = 485 nm, FWHM = 21.1 nm). As the K ion content increases, the space group of the phosphor evolves from 4/ to 41/. The complete replacement of Rb by K results in the KNa(LiSiO):Eu cyan phosphor, which shows excellent thermal stability (the comprehensive emission loss is only 8% at 150 °C) and can be used to fill the cyan light gap in white LED devices. By adding the KNa(LiSiO):Eu cyan phosphor in packaging with yellow and red phosphors, the color rendering index is increased from 90.2 to 97.1 and the correlated color temperature improved to 3658 K. These results indicate that the cyan phosphor has important application value in full-spectrum white LEDs.
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http://dx.doi.org/10.1039/d2dt01896aDOI Listing
August 2022

m 6  Aexpress-BHM: predicting m6A regulation of gene expression in multiple-groups context by a Bayesian hierarchical mixture model.

Brief Bioinform 2022 07;23(4)

Henan University of Science and Technology Affiliated First Hospital.

As the most abundant RNA modification, N6-methyladenosine (m6A) plays an important role in various RNA activities including gene expression and translation. With the rapid application of MeRIP-seq technology, samples of multiple groups, such as the involved multiple viral/ bacterial infection or distinct cell differentiation stages, are extracted from same experimental unit. However, our current knowledge about how the dynamic m6A regulating gene expression and the role in certain biological processes (e.g. immune response in this complex context) is largely elusive due to lack of effective tools. To address this issue, we proposed a Bayesian hierarchical mixture model (called m6Aexpress-BHM) to predict m6A regulation of gene expression (m6A-reg-exp) in multiple groups of MeRIP-seq experiment with limited samples. Comprehensive evaluations of m6Aexpress-BHM on the simulated data demonstrate its high predicting precision and robustness. Applying m6Aexpress-BHM on three real-world datasets (i.e. Flaviviridae infection, infected time-points of bacteria and differentiation stages of dendritic cells), we predicted more m6A-reg-exp genes with positive regulatory mode that significantly participate in innate immune or adaptive immune pathways, revealing the underlying mechanism of the regulatory function of m6A during immune response. In addition, we also found that m6A may influence the expression of PD-1/PD-L1 via regulating its interacted genes. These results demonstrate the power of m6Aexpress-BHM, helping us understand the m6A regulatory function in immune system.
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http://dx.doi.org/10.1093/bib/bbac295DOI Listing
July 2022

Network pharmacology and bioinformatics analysis identified essential genes of Jingulian in the treatment of rheumatoid arthritis and COVID-19.

Ann Transl Med 2022 Jun;10(11):635

Department of Laboratory Medicine, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China.

Background: Patients with rheumatoid arthritis (RA) may be more susceptible to infection by coronavirus disease-19 (COVID-19) due to immune system dysfunction. However, there are still insufficient treatment strategies for patients with RA and COVID-19. Since Jingulian is a traditional Chinese medicine (TCM) with anti-viral and immune regulatory functions, our study aims to explore the detailed mechanisms of Jingulian in treating patients with RA and COVID-19.

Methods: All the components of Jingulian were retrieved from pharmacology databases. Then, a series of network pharmacology-based analyses and molecular docking were used to understand the molecular functions, core targets, related pathways, and potential therapeutic targets of Jingulian in patients with RA/COVID-19.

Results: A total of 93 genes were identified according to the disease-compound-target network. We investigated that the main targets, signaling pathways, and biological functions of Jingulian in RA and COVID-19. Our results indicated that Jingulian may treat patients with RA/COVID-19 through immune processes and viral processes. Moreover, the results of molecular docking revealed that tormentic acid was one of the top compounds of Jingulian, which had high affinity with Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and epidermal growth factor receptor (EGFR) in patients with RA/COVID-19. Furthermore, 5 core targets of Jingulian were also identified, including JAK1, Janus kinase 2 (JAK2), STAT3, lymphocyte specific protein tyrosine kinase (LCK), and EGFR.

Conclusions: Tormentic acid in Jingulian may regulate JAK1, STAT3, and EGFR, and might play a critical role in RA/COVID-19.
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http://dx.doi.org/10.21037/atm-22-1665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263763PMC
June 2022

MiR-135b improves proliferation and regulates chemotherapy resistance in ovarian cancer.

J Mol Histol 2022 Jul 6. Epub 2022 Jul 6.

Department of Pathology, The First Hospital, Jilin University, Changchun City, Jilin Province, 130021, China.

MicroRNAs act as regulators in ovarian tumorigenesis and progression by involving different molecular pathways. Here, we examined the role of miR-135b on growth, chemotherapy resistance in OVCAR3 and SKOV3 ovarian cancer cells. MTT assay was performed to examine proliferation. Transwell migration and matrigel invasion assays were used to assess migration and invasion. Caspase-Glo3/7 assay was carried out to evaluate apoptosis. The dual-luciferase reporter assay was performed to validate the putative binding site. Meanwhile, the miR-135b levels in human ovarian cancer tissue were detected by qPCR assay. Overexpression of miR-135b increased growth, and improved migration and invasion in ovarian cancer cells. Meanwhile, overexpression of miR-135b decreased the cisplatin treatment sensitivity in OVCAR3 and SKOV3 cells. The cisplatin-induced apoptosis was decreased by miR-135b. Furthermore, miR-135b could alter epithelial to mesenchymal transition (EMT) associated proteins expression including E-cadherin, N-cadherin, snail and Vimentin in ovarian cancer cells. Further study demonstrated aberrant expression of miR-135b regulated PTEN and p-AKT expression in ovarian cancer cells. The expression level of miR-135b was increased in human ovarian cancer tissue, compared with normal ovary tissue. MiR-135b involves in tumorigenesis and progression in ovarian cancer cells, and might serve as a promising biomarker to predict chemotherapy sensitivity and prognosis in ovarian cancer.
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http://dx.doi.org/10.1007/s10735-022-10080-yDOI Listing
July 2022

Development and validation of a blood-based genomic mutation signature to predict the clinical outcomes of atezolizumab therapy in NSCLC.

Lung Cancer 2022 Aug 28;170:148-155. Epub 2022 Jun 28.

National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China. Electronic address:

Objectives: We designed this study to develop a blood-based genomic mutation signature (bGMS) model for predicting the efficacy of atezolizumab therapy in non-small cell lung cancer (NSCLC) in a non-invasive manner.

Materials And Methods: Patients with NSCLC treated with atezolizumab from POPLAR and OAK clinical trials were included in our study. OAK cohort was defined as the training group, and POPLAR cohort was defined as the validation group. LASSO Cox regressions were applied to the training group to develop the gene mutation signature model to predict the overall survival (OS). Then the model was validated in the validation group. The combined impact of bGMS and other factors was explored with multivariable Cox regression.

Results: A bGMS risk model including 15 genes was established to classify patients into high-bGMS and low-bGMS groups. High-bGMS patients had shorter overall survival (OS) and progression-free survival (PFS) compared with low-bGMS in both training cohort (OS 7.9 vs. 19.9 months, p < 0.0001; PFS 1.7 vs. 4 months, p = 0.011) and validation cohort (OS 8.4 vs. 18.6 months, p = 0.0019; PFS 1.5 vs. 4.4 months, p = 0.013). The bGMS was superior to the blood tumor mutation burden (bTMB), LAF-bTMB, MSAF, PD-L1 expression, and a 5-genomic mutation signature in predicting OS for patients receiving atezolizumab. In addition, low-bGMS patients receiving atezolizumab therapy had a better OS rate compared with those receiving docetaxel therapy in both training (P < 0.0001) and validation groups (P = 0.018). Multivariate Cox regression analysis showed that bGMS was an independent prognostic factor on OS and PFS for patients receiving atezolizumab. Furthermore, a nomogram was developed to combine bGMS with the clinical characteristics to improve the predictive power further.

Conclusion: bGMS could predict OS benefit for patients with NSCLC receiving atezolizumab therapy. BGMS and other non-invasive clinical characteristics can be combined to develop a more accurate model.
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http://dx.doi.org/10.1016/j.lungcan.2022.06.016DOI Listing
August 2022

Actin-bundling protein fimbrin regulates pathogenicity via organizing F-actin dynamics during appressorium development in Colletotrichum gloeosporioides.

Mol Plant Pathol 2022 Jul 5. Epub 2022 Jul 5.

Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresource, Key Laboratory of Biotechnology of Salt Tolerant Crops of Hainan Province, College of Tropical Crops, Hainan University, Haikou, China.

Anthracnose caused by Colletotrichum gloeosporioides leads to serious economic loss to rubber tree yield and other tropical crops. The appressorium, a specialized dome-shaped infection structure, plays a crucial role in the pathogenesis of C. gloeosporioides. However, the mechanism of how actin cytoskeleton dynamics regulate appressorium formation and penetration remains poorly defined in C. gloeosporioides. In this study, an actin cross-linking protein fimbrin homologue (CgFim1) was identified in C. gloeosporioides, and the knockout of CgFim1 led to impairment in vegetative growth, conidiation, and pathogenicity. We then investigated the roles of CgFim1 in the dynamic organization of the actin cytoskeleton. We observed that actin patches and cables localized at the apical and subapical regions of the hyphal tip, and showed a disc-to-ring dynamic around the pore during appressorium development. CgFim1 showed a similar distribution pattern to the actin cytoskeleton. Moreover, knockout of CgFim1 affected the polarity of the actin cytoskeleton in the hyphal tip and disrupted the actin dynamics and ring structure formation in the appressorium, which prevented polar growth and appressorium development. The CgFim1 mutant also interfered with the septin structure formation. This caused defects in pore wall overlay formation, pore contraction, and the extension of the penetration peg. These results reveal the mechanism by which CgFim1 regulates the growth and pathogenicity of C. gloeosporioides by organizing the actin cytoskeleton.
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http://dx.doi.org/10.1111/mpp.13242DOI Listing
July 2022

Safety and immunogenicity of COVID-19 vaccination among liver transplant recipients in China.

Hepatobiliary Pancreat Dis Int 2022 Jun 23. Epub 2022 Jun 23.

Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao 266000, China; Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao 266000, China. Electronic address:

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http://dx.doi.org/10.1016/j.hbpd.2022.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9222404PMC
June 2022

Clinicopathologic association and prognostic impact of microcystic, elongated and fragmented pattern invasion, combined with tumor budding in endometrioid endometrial cancer.

J Obstet Gynaecol Res 2022 Jun 29. Epub 2022 Jun 29.

Department of Obstetrics and Gynecology, Xuzhou Central Hospital affiliated to Nanjing University of Traditional Chinese Medicine, Xuzhou, China.

Aim: As a special invasive pattern seen in low-grade endometrial carcinoma, microcystic, elongated and fragmented (MELF) pattern is related to lymph node metastasis. Tumor budding (TB) is another histological marker in many cancers associated with tumor aggressiveness. Herein, we evaluated the impact of MELF pattern combined with TB about clinicopathological features and prognosis in endometrioid endometrial cancer (EEC). To verify the relationship between the two morphological markers and microsatellite status in EEC, the primary mismatch repair (MMR) proteins were detected by immunohistochemistry.

Methods: One hundred and seventy-two cases of ECC diagnosed between 2011 and 2016 were reviewed with a median follow up of 47.5 months. MELF pattern and TB were examined on all H&E-stained slides. Primary MMR proteins (MLH1, MSH2, MSH6, and PMS2) were also detected.

Results: Based on MELF pattern and TB, 172 patients were divided into the following four groups: MELF(-)/TB(+) (n = 41), MELF(+)/TB(-) (n = 15), MELF(+)/TB(+) (n = 20), and MELF(-)/TB(-) (n = 96). Adverse pathological features were observed in the MELF(+)/TB(+) group: 70% presented deep muscular infiltration, 65% were lymphovascular space invasion, and 25% suffered lymph node metastasis. The proportion of MMR deficient in MELF(+)/TB(-) group was the highest (66.7%). The progression-free survival (PFS) and overall survival (OS) among the four groups were significantly different. MELF(+)/TB(+) group showed the worst PFS and OS. As univariate and multivariate survival analyses revealed, the combination of MELF pattern and TB was confirmed as an independent predictor of poor prognosis.

Conclusions: Our research demonstrates that MELF pattern combined with TB, as an independent predictor of adverse outcome, is associated with adverse pathological features, which facilitates better understanding of EEC tumor behavior and more precise prognosis without additional medical expense.
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http://dx.doi.org/10.1111/jog.15335DOI Listing
June 2022

A Hybrid volume-Surface Integral Equation Method for Rapid Electromagnetic Simulations in MRI.

IEEE Trans Biomed Eng 2022 Jun 27;PP. Epub 2022 Jun 27.

Objective: We developed a hybrid volume surface integral equation (VSIE) method based on domain decomposition to perform fast and accurate magnetic resonance imaging (MRI) simulations that include both remote and local conductive elements.

Methods: We separated the conductive surfaces present in MRI setups into two domains and optimized electromagnetic (EM) modeling for each case. Specifically, interactions between the body and EM waves originating from local radiofrequency (RF) coils were modeled with the precorrected fast Fourier transform, whereas the interactions with remote conductive surfaces (RF shield, scanner bore) were modeled with a novel cross tensor train-based algorithm. We compared the hybrid-VSIE with other VSIE methods for realistic MRI simulation setups.

Results: The hybrid-VSIE was the only practical method for simulation using 1 mm voxel isotropic resolution (VIR). For 2 mm VIR, our method could be solved at least 23 times faster and required 760 times lower memory than traditional VSIE methods.

Conclusion: The hybrid-VSIE demonstrated a marked improvement in terms of convergence times of the numerical EM simulation compared to traditional approaches in multiple realistic MRI scenarios.

Significance: The efficiency of the novel hybrid-VSIE method could enable rapid simulations of complex and comprehensive MRI setups.
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http://dx.doi.org/10.1109/TBME.2022.3186235DOI Listing
June 2022

PTPRN Serves as a Prognostic Biomarker and Correlated with Immune Infiltrates in Low Grade Glioma.

Brain Sci 2022 Jun 10;12(6). Epub 2022 Jun 10.

Department of Neurosurgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, China.

Background: Glioma is one of the most common malignant tumors of the central nervous system. Immune infiltration of tumor microenvironment was associated with overall survival in low grade glioma (LGG). However, effects of Tyrosine phosphatase receptor type N (PTPRN) on the progress of LGG and its correlation with tumor infiltration are unclear.

Methods: Here, datasets of LGG were from The Cancer Genome Atlas (TCGA) and normal samples were from GTEx dataset. Gepia website and Human Protein Atlas (HPA) Database were used to analyze the mRNA and protein expression of PTPRN. We evaluated the influence of PTPRN on survival of LGG patients. MethSurv was used to explore the expression and prognostic patterns of single CpG methylation of PTPRN gene in LGG. The correlations between the clinical information and PTPRN expression were analyzed using logistic regression and Multivariate Cox regression. We also explored the correlation between PTPRN expression and cancer immune infiltration by TIMER. Gene set enrichment analysis (GSEA) was formed using TCGA RNA-seq datasets.

Results: PTPRN mRNA and protein expression decreased in LGG compared to normal brain tissue in TCGA and HPA database. Kaplan-Meier analysis showed that the high expression level of PTPRN correlated with a good overall survival (OS) of patients with LGG. The Multivariate Cox analysis demonstrated that PTPRN expression and other clinical-pathological factors (age, WHO grade, IDH status, and primary therapy outcome) significantly correlated with OS of LGG patients. The DNA methylation pattern of PTPRN with significant prognostic value were confirmed, including cg00672332, cg06971096, cg01382864, cg03970036, cg10140638, cg16166796, cg03545227, and cg25569248. Interestingly, PTPRN expression level significantly negatively correlated with infiltrating level of B cell, CD4+ T cells, Macrophages, Neutrophils, and DCs in LGG. Finally, GSEA showed that signaling pathways, mainly associated with tumor microenvironment and immune cells, were significantly enriched in PTPRN high expression.

Conclusion: PTPRN is a potential biomarker and correlates with tumor immune infiltration in LGG.
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http://dx.doi.org/10.3390/brainsci12060763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221056PMC
June 2022

Recent advances in the development of EGFR degraders: PROTACs and LYTACs.

Eur J Med Chem 2022 Sep 16;239:114533. Epub 2022 Jun 16.

Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address:

Epidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting Chimeras (PROTACs) and LYsosome Targeting Chimeras (LYTACs), take advantages of protein destruction mechanism in cells, which make up for shortcomings of traditional small molecular occupancy-driven inhibitors. PROTACs based heterobifunctional EGFR degraders were recently developed by making use of wild-type (WT) and mutated EGFR inhibitors. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the inhibitors that have been developed against WT/mutated EGFR, and then mainly focuses on the recent advances of EGFR-targeting degraders along with its limitations and unlimited prospects.
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http://dx.doi.org/10.1016/j.ejmech.2022.114533DOI Listing
September 2022

Blockade of TIM-3 and PD-1 enhances the antitumor effects of MAGE-A11 antigen-specific cytotoxic T lymphocytes.

Bull Cancer 2022 Jun 13. Epub 2022 Jun 13.

Clinical Laboratory, The Third Hospital of Hebei Medical University, Shijiazhuang 050011, PR China. Electronic address:

Cancer immunotherapy is an attractive approach for antigen-specific T cell-mediated antitumor therapy, especially for the induction of cytotoxic T lymphocytes (CTLs). An human leukocyte antigen (HLA)-A2-restricted melanoma-associated antigen-A11 (MAGE-A11) peptide was developed that exhibited a potent capacity to induce cytotoxicity towards MAGE-A11-positive breast cancer cells by activating CTLs. However, this antitumor immune response can be suppressed by inhibitory pathways. Programmed death-1 (PD-1) and T cell immunoglobulin domain and mucin domain 3 (TIM-3) pathways are two important pathways involved in the tumor-mediated immune suppression. The present study aimed to augment the efficacy of MAGE-A11 antigen-specific CTLs via blocking PD-1 and TIM-3. The results showed that the expression levels of PD-1 and TIM-3 were unregulated during T cell induction, expansion and target cell killing. Blockade of PD-1 and TIM-3 modulated T cell proliferation, transformation and survival. In addition, treatment of cells with antibodies against PD-1 and TIM-3 enhanced the cytotoxicity of MAGE-A11 antigen-specific CTLs against breast cancer cells. The aforementioned findings suggested that MAGE-A11 antigen-specific CTLs accompanied by PD-1 and TIM-3 blockade could be considered as a potential therapy approach for breast cancer.
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http://dx.doi.org/10.1016/j.bulcan.2022.04.005DOI Listing
June 2022

Performance evaluation of a laboratory-developed light-initiated chemiluminescence assay for quantification of egg white-specific IgE.

J Clin Lab Anal 2022 Jul 16;36(7):e24544. Epub 2022 Jun 16.

School of Medical Laboratory, Tianjin Medical University, Tianjin, China.

Background: Specific IgE (sIgE) testing has become one of the most important tools for diagnosing IgE-mediated food allergy. Enzyme-linked immunosorbent assay (ELISA) and dot-enzyme-linked immunosorbent assay (Dot-ELISA) have been used to measure sIgE in clinical widely. Light-initiated chemiluminescence assay (LICA) is a new method for measuring allergen-sIgE. We aimed to establish a LICA method for quantitative detection of egg white-sIgE and evaluate its performances.

Methods: The best chemibeads coupling method in detecting egg white-sIgE was selected, and a LICA method for quantitative detection of egg white-sIgE was established. The precision study was performed according to Clinical and Laboratory Standards Institute (CLSI) EP5-A2. Detection capability which contains limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ) was evaluated according to National Health Commission of the People's Republic of China (NHC) WS/T 514-2017. Linear range was evaluated according to CLSI EP6-A. All data were analyzed using SPSS software.

Results: Precision contains repeatability and intermediate precision. The CV of repeatability ranged from 2.72% to 7.29%, and the CV of intermediate precision ranged from 4.93% to 8.64%. The LoB, LoD, and LoQ of the assay were 0.000 kUA/L, 0.053 kUA/L, and 0.076 kUA/L. The assay linear range was 0.076-34.125 kU /L (r = 0.9979 ≥ 0.9900).

Conclusion: This laboratory-developed LICA method can detect egg white-sIgE, and performance meets clinical requirements. This method shows rapid turnaround cycles and high sensitivity. It can be used as an alternative method for clinical detection of egg white-sIgE.
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http://dx.doi.org/10.1002/jcla.24544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279973PMC
July 2022

Evaluation of Right Ventricular Myocardial Mechanics by 2- and 3-Dimensional Speckle-Tracking Echocardiography in Patients With an Ischemic or Non-ischemic Etiology of End-Stage Heart Failure.

Front Cardiovasc Med 2022 25;9:765191. Epub 2022 May 25.

Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: The aims of our study were (1) to assess the right ventricular (RV) myocardial mechanics by two-dimensional (2D) and three-dimensional (3D) speckle-tracking echocardiography (STE) in patients with an ischemic or non-ischemic etiology of end-stage heart failure (HF) and (2) to explore which RV index evaluated by 2D- and 3D-STE was the most powerful indicator for identifying the ischemic and non-ischemic etiologies of end-stage HF.

Methods: A total of 96 patients with left ventricular ejection fraction (LVEF) < 30% were enrolled in our study: 42 patients (mean age, 52 ± 10 years; 9.5% female) with ischemic cardiomyopathy and 54 patients (mean age, 46 ± 14 years; 16.7% female) with non-ischemic cardiomyopathy. A total of 45 healthy subjects (mean age, 46 ± 13 years; 24.4% female) served as controls. The longitudinal strain of the RV free wall (RVFWLS) was determined by both 2D- and 3D-STE.

Results: Compared to controls, patients with an ischemic or non-ischemic etiology of end-stage HF had lower 2D-RVFWLS, 3D-RVFWLS and RV ejection fraction (RVEF) values ( < 0.05). Patients with non-ischemic cardiomyopathies (NICMs) had significantly lower 3D-RVFWLS and RVEF values than in those with ischemic cardiomyopathies (ICMs), whereas 2D-RVFWLS and conventional RV function parameters did not differ between the two subgroups. RVEF was highly related to 3D-RVFWLS ( = 0.72, < 0.001), modestly related to 2D-RVFWLS ( = 0.51, < 0.001), and weakly related to conventional RV function indices ( = -0.26 to 0.46, < 0.05). Receiver operating characteristic curve analysis revealed that the optimal 3D-RVFWLS cut-off value to distinguish NICM from ICM patients was -14.78% (area under the curve: 0.73, < 0.001), while 2D-RVFWLS and conventional RV echocardiographic parameters did not.

Conclusion: Our study demonstrated the superiority of 3D-RVFWLS over 2D-RVFWLS and conventional RV function indices in identifying the ischemic and non-ischemic etiologies of end-stage HF. These findings support the idea that 3D-RVFWLS may be a promising non-invasive imaging marker for distinguishing NICM from ICM.
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http://dx.doi.org/10.3389/fcvm.2022.765191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174453PMC
May 2022

The Association of Nocturnal Blood Pressure Patterns and Other Influencing Factors With Lacunes and Enlarged Perivascular Spaces in Hypertensive Patients.

Front Neurol 2022 23;13:879764. Epub 2022 May 23.

Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Purpose: Nocturnal blood pressure dipping patterns have been associated with an increased risk of Cerebral Small Vessel Disease (CSVD), which has not been well-studied. This study is aimed to explore the association of dipping patterns and other factors with lacunes and enlarged perivascular spaces (EPVS) in patients with hypertension.

Methods: We enrolled a total of 1,322 patients with essential hypertension in this study. Magnetic resonance imaging (MRI) scans and 24-h ambulatory blood pressure (BP) monitoring were completed. Nocturnal BP decline was calculated, and then dipping patterns were classified. Patients were classified into four groups according to the performance of lacunes and EPVS in the MRI scan for statistical analysis.

Results: (1) Nocturnal BP decline showed independent negative correlation with both lacunes and EPVS while mean systolic BP (mSBP) level showed an independent positive correlation with them ( < 0.05). (2) The frequency of reverse-dippers in the control group was significantly lower than that in other groups; the frequency of non-dippers in the lacunes group and EPVS group was significantly lower than that in the control group; the frequency of extreme-dippers in the EPVS group was significantly higher than that in the mixed (lacunes with EPVS) group ( < 0.05).

Conclusions: Both mSBP and dipping patterns might play an important role in developing lacunes and EPVS in patients with hypertension.
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http://dx.doi.org/10.3389/fneur.2022.879764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168463PMC
May 2022

Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties.

J Enzyme Inhib Med Chem 2022 Dec;37(1):1537-1555

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.

The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC values and significant selectivity towards other S-adenosyl--methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.
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http://dx.doi.org/10.1080/14756366.2022.2079640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186373PMC
December 2022

Identification of novel non-HFE mutations in Chinese patients with hereditary hemochromatosis.

Orphanet J Rare Dis 2022 06 6;17(1):216. Epub 2022 Jun 6.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, 95 Yong-An Road, Beijing, 100050, China.

Backgrounds: Hereditary hemochromatosis (HH) is mainly caused by homozygous p.C282Y mutations in HFE in the Caucasians. We recently reported non-HFE mutations constitute the major cause of HH in Chinese. However, there is still a relatively high proportion of cases with primary iron overload from unexplained causes. We aimed to explore novel non-HFE mutations in Chinese patients with primary iron overload.

Methods: Whole exome sequence was conducted to screen mutations in novel HH-related genes in the 9 cases with unexplained primary iron overload. Then the representative candidate genes were screened for mutations in another cohort of 18 HH cases. The biological function of the selected genes and variants were analyzed in vitro.

Results: Whole exome sequencing of 9 cases with unexplained primary iron overload identified 42 missense variants in 40 genes associated with iron metabolism pathway genes such as UBE2O p.K689R and PCSK7 p.R711W. Subsequent Sanger sequencing of the UBE2O and PCSK7 genes in the 27 cases with primary iron overload identified p.K689R in UBE2O, p.R711W and p.V143F in PCSK7 at frequency of 2/27,1/27 and 2/27 respectively. In vitro siRNA interference of UBE2O and PCSK7 resulted in down-regulated HAMP mRNA expression. Adenovirus generation of UBE2O p.K689R in cell lines resulted in increased expression of SMAD6 and SMAD7 and downregulation of p-SMAD1/5 and HAMP expression, and the reduction of hepcidin level.

Conclusions: Our study identified a series of novel candidate non-HFE mutations in Chinese patients with HH. These may provide insights into the genetic basis of unexplained primary iron overload.
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http://dx.doi.org/10.1186/s13023-022-02349-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9169345PMC
June 2022

Acute percheron infarction: a precision learning.

BMC Neurol 2022 Jun 4;22(1):207. Epub 2022 Jun 4.

Department of Radiology, First Hospital of Jilin University, No. 1, Xinmin Street, Changchun, 130021, Jilin Province, China.

Background: So far, the diagnosis of acute artery of percheron (AOP) infarction is uncommon. In this study, patients with acute AOP infarction were studied to explore the relationship of imaging findings, clinical manifestations and prognosis of acute AOP infarction.

Materials: A total of 23 patients with acute AOP infarction in our institution from 2014 to 2019 were reviewed retrospectively. All cases were evaluated by computed tomography (CT) and magnetic resonance imaging (MRI). The modified Rankin scale (MRS), blood examination, electrocardiogram and transthoracic echocardiography were used for detailed clinical and prognostic evaluation. All standard risk factors for these patients were recorded. The MRS scores were performed 90 days after discharge.

Results: Four different types of acute AOP infarction were identified: (a) bilateral paramedian thalamic infarction (BPTI, 52%); (b) bilateral paramedian thalamic with rostral midbrain infarction (BPTRMI, 30%), (c) bilateral paramedian and anterior thalamic infarction (BPATI, 13%), and (d) bilateral paramedian thalamic with red nuclei infarction (BPTRNI, 4%). These patients had consciousness disorder, memory dysfunctions, vertical gaze paresis and mesencephalothalamic syndrome. The 65% of patients with BPTI and BPATI experienced relatively good functional recovery and could carry out daily life activities (MRS score ≤ 2). However, patients with BPTRMI may have an unfavorable outcome.

Conclusions: Although the clinical features are variable, DWI or ADC map can improve the diagnosis of acute AOP infarction patterns. Acute AOP occlusion requires immediate diagnosis and treatment to obtain more favorable outcome and avoid additional unnecessary procedures.
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http://dx.doi.org/10.1186/s12883-022-02735-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166501PMC
June 2022

Accurate 16S Absolute Quantification Sequencing Revealed Vaginal Microecological Composition and Dynamics During Mixed Vaginitis Treatment With Fufang FuRong Effervescent Suppository.

Front Cell Infect Microbiol 2022 13;12:883798. Epub 2022 May 13.

Department of Obstetrics and Gynecology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.

Background: The diagnosis and treatment of mixed vaginitis are more complicated than single pathogenic infections, and there may be adverse reactions and several contraindications to conventional antibiotic therapy. Therefore, this study aimed to evaluate the preliminary effects of Fufang Furong Effervescent Suppository for the management of aerobic vaginitis (AV) mixed with bacterial vaginosis (BV) using Accurate 16S absolute quantification sequencing (Accu16S).

Methods: In the present randomized, blind, multi-center clinical trial, women (20 to 55 years) who had received a diagnosis of AV+BV were randomly assigned into clindamycin positive control (n = 41) and Fufang Furong Effervescent Suppository (n = 39) groups. The follow-up occurred in three time periods (V1: -2~0 days; V2: 15-17 days; V3: 40 ± 3 days). At each visit, two vaginal swabs, one for clinical evaluation and one for laboratory examination, were taken from each patient. The Nugent score, Donders' score, drug-related complications, recurrence rates, and microecological changes of vaginal swabs were assessed in the time three periods.

Results: At baseline, the two groups were similar in frequency of presentation with vaginal burning, odor, abnormal discharge, and itching. No meaningful differences in Nugent and Donders' scores were detected between the two groups at stage V2 (Nugent: = 0.67; Donders': 0.85) and V3 (Nugent: = 0.97; Donders: = 0.55). The Furong group presented fewer complications compared to the Clindamycin group. However, this difference was not statistically significant ( = 0.15). Additionally, Accu16S indicated that the total abundance of bacteria in both groups sharply decreased in stage V2, but slightly increased in V3. In stage V3, the absolute abundance of in the Furong group was considerably higher compared to untreated samples ( < 0.05). On the other hand, no momentous increase was detected in the Clindamycin group ( > 0.05).

Conclusion: Fufang Furong Effervescent Suppository can be as effective as clindamycin cream in the management of AV+BV while may restore the vagina microecosystem better.
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http://dx.doi.org/10.3389/fcimb.2022.883798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136393PMC
May 2022

The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation.

BMC Pharmacol Toxicol 2022 05 31;23(1):33. Epub 2022 May 31.

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China.

Background: Tamoxifen treatment may induce dysregulation of estrogen homeostasis, leading to the occurrence of related adverse reactions. However, the potential mechanisms are still unclear. The purpose of the present study was to uncover whether tamoxifen treatment would act on estrogen metabolism-related biological enzymes and the regulatory effect on estrogen homeostasis to clarify the key factors and potential mechanisms of adverse reactions caused by long-term use of tamoxifen.

Method: Female SD rats were administrated with tamoxifen CMC-Na solution (p.o.) once daily for four weeks and then housed at room temperature. Serum, breast, liver, uterus, and ovarian tissues were obtained, and the effects of tamoxifen administration on estrogen homeostasis, the expression, and activity of estrogen metabolic enzyme were evaluated.

Results: Compared with the control group, the estrogen homeostasis was disturbed and the expression and activity of UGT2B1 (homology with human UGT2B7) were significantly reduced in the rats administrated with tamoxifen. The inhibitory effect of tamoxifen on UGT2B7 was dominated by hydrophobic and π-π stacking interactions, resulting in a concentration-dependent inhibition of UGT2B7 activity by tamoxifen and the imbalance of ligand-activated transcription factors, leading to abnormal regulation of UGT2B and disturbance of estrogen homeostasis, which in turn led to adverse reactions of tamoxifen.

Conclusion: We established links between estrogen metabolism and tamoxifen administration and we proposed that the UGT2B inhibition was involved in the disturbance of estrogen homeostasis and the occurrence of tamoxifen-related adverse reactions.
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http://dx.doi.org/10.1186/s40360-022-00574-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9158366PMC
May 2022

Regulator of G Protein Signaling Contributes to the Development and Aflatoxin Biosynthesis in Aspergillus flavus through the Regulation of Gα Activity.

Appl Environ Microbiol 2022 06 31;88(12):e0024422. Epub 2022 May 31.

State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Key Laboratory of Pathogenic Fungi and Mycotoxins, School of Life Sciences, Fujian Agriculture and Forestry Universitygrid.256111.0, Fuzhou, Fujian, China.

Heterotrimeric G-proteins play crucial roles in growth, asexual development, and pathogenicity of fungi. The regulator of G-protein signaling (RGS) proteins function as negative regulators of the G proteins to control the activities of GTPase in Gα subunits. In this study, we functionally characterized the six RGS proteins (i.e., RgsA, RgsB, RgsC, RgsD, RgsE, and FlbA) in the pathogenic fungus Aspergillus flavus. All the aforementioned RGS proteins were also found to be functionally different in conidiation, aflatoxin (AF) biosynthesis, and pathogenicity in A. flavus. Apart from FlbA, all other RGS proteins play a negative role in regulating both the synthesis of cyclic AMP (cAMP) and the activation of protein kinase A (PKA). Additionally, we also found that although RgsA and RgsE play a negative role in regulating the FadA-cAMP/PKA pathway, they function distinctly in aflatoxin biosynthesis. Similarly, RgsC is important for aflatoxin biosynthesis by negatively regulating the GanA-cAMP/PKA pathway. PkaA, which is the cAMP-dependent protein kinase catalytic subunit, also showed crucial influences on A. flavus phenotypes. Overall, our results demonstrated that RGS proteins play multiple roles in the development, pathogenicity, and AF biosynthesis in A. flavus through the regulation of Gα subunits and cAMP-PKA signals. RGS proteins, as crucial regulators of the G protein signaling pathway, are widely distributed in fungi, while little is known about their roles in Aspergillus flavus development and aflatoxin. In this study, we identified six RGS proteins in A. flavus and revealed that these proteins have important functions in the regulation of conidia, sclerotia, and aflatoxin formation. Our findings provide evidence that the RGS proteins function upstream of cAMP-PKA signaling by interacting with the Gα subunits (GanA and FadA). This study provides valuable information for controlling the contamination of A. flavus and mycotoxins produced by this fungus in pre- and postharvest of agricultural crops.
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http://dx.doi.org/10.1128/aem.00244-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238415PMC
June 2022

An analysis report on the application of immune checkpoint inhibitors after liver transplantation.

Ther Adv Chronic Dis 2022 19;13:20406223221099334. Epub 2022 May 19.

Division of Hepatology, Liver Disease Center, Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, No. 59 Hai'er Road, Laoshan District, Qingdao City 266600, Shandong Province, China.

Up to now, a variety of immune checkpoint inhibitors (ICIs) have been proved to have good therapeutic effects in the treatment of hepatocellular carcinoma (HCC). However, the effects of their applications in liver transplant (LT) recipients are still unclear. In this analysis report, the clinical applications and therapeutic effects of ICIs on LT recipients with hepatic tumor recurrence or carcinoma based on eight databases, including PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Infrastructure, Wanfang Data, and CQVIP, were investigated. And the prior treatment, disease response, adverse reactions, and prognosis of patients with malignant tumors after LT and receiving ICI treatments were analyzed. After screening, a total of 28 articles with 47 recipients on the application of ICIs after LT were included. In these patients, their median age was 57 (14-71) years and the main type of tumor after LT was HCC (59.6%). The overall remission rate following ICI treatment was 29.8% (14/47) and the disease progression rate was 68.1% (32/47). Among all these patients, 31.9% (15/47) of patients had immune rejection; the median survival time was 6.5 (0.3-48) months, and the fatality rate was 61.7% (29/47). Considering that the therapeutic effect of ICIs in LT recipients with HCC recurrence or carcinoma is not ideal, ICI treatment should be carefully considered for LT patients, and further research is needed.
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http://dx.doi.org/10.1177/20406223221099334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127875PMC
May 2022

Th1-Like Treg Cells Are Increased But Deficient in Function in Rheumatoid Arthritis.

Front Immunol 2022 4;13:863753. Epub 2022 May 4.

Department of Clinical Immunology, Chinese People's Liberation Army. (PLA) Specialized Research Institute of Rheumatoid & Immunology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Objectives: This study aimed to investigate the changes in quantity and function of T helper (Th)-like T regulatory (Treg) cell subsets in peripheral blood (PB) and synovial fluid (SF) of rheumatoid arthritis (RA) patients and to understand their relationship with disease activity.

Methods: A total of 86 RA patients and 76 gender and age-matched healthy controls (HC) were enrolled in this study. Th-like Treg frequency and function were determined using flow cytometry. The inhibitory function of Th-like Treg cells was detected using an co-culture suppression assay.

Results: The proportion and absolute number of Th1-like Treg cells from RA PB and RA SF were significantly higher than those of HC PB. In RA SF, the proportions of Treg cells and Th1-like Treg cells were significantly lower in the elevated erythrocyte sedimentation rate or the C-Reactive Protein group, and in the positive groups of anti-CCP antibody and anti-MCV antibody. Additionally, the proportions of Treg cells and Th1-like Treg cells from RA SF were negatively correlated with disease activity. However, the expression levels of CD73 and TGF-β1 in Th1-like Treg cells were decreased, and these Treg cells could not effectively inhibit the proliferation of effector T (Teff) cells.

Conclusion: Our data indicate that Th1-like Treg cells are the predominant Treg cell subset in RA SF, but their suppressive function is defective. Improving the function of Th1-like Treg cells may control inflammation in joints and provide new strategies for Treg-targeted therapies in RA.
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http://dx.doi.org/10.3389/fimmu.2022.863753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114761PMC
May 2022

Deciphering clonal dynamics and metastatic routines in a rare patient of synchronous triple-primary tumors and multiple metastases with MPTevol.

Brief Bioinform 2022 May 23. Epub 2022 May 23.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.

Multiple primary tumor (MPT) is a special and rare cancer type, defined as more than two primary tumors presenting at the diagnosis in a single patient. The molecular characteristics and tumorigenesis of MPT remain unclear due to insufficient approaches. Here, we present MPTevol, a practical computational framework for comprehensively exploring the MPT from multiregion sequencing (MRS) experiments. To verify the utility of MPTevol, we performed whole-exome MRS for 33 samples of a rare patient with triple-primary tumors and three metastatic sites and systematically investigated clonal dynamics and metastatic routines. MPTevol assists in comparing genomic profiles across samples, detecting clonal evolutionary history and metastatic routines and quantifying the metastatic history. All triple-primary tumors were independent origins and their genomic characteristics were consistent with corresponding sporadic tumors, strongly supporting their independent tumorigenesis. We further showed two independent early monoclonal seeding events for the metastases in the ovary and uterus. We revealed that two ovarian metastases were disseminated from the same subclone of the primary tumor through undergoing whole-genome doubling processes, suggesting metastases-to-metastases seeding occurred when tumors had similar microenvironments. Surprisingly, according to the metastasis timing model of MPTevol, we found that primary tumors of about 0.058-0.124 cm diameter have been disseminating to distant organs, which is much earlier than conventional clinical views. We developed MPT-specialized analysis framework MPTevol and demonstrated its utility in explicitly resolving clonal evolutionary history and metastatic seeding routines with a rare MPT case. MPTevol is implemented in R and is available at https://github.com/qingjian1991/MPTevol under the GPL v3 license.
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http://dx.doi.org/10.1093/bib/bbac175DOI Listing
May 2022
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