Publications by authors named "Yuan Ji"

580 Publications

Giant oscillatory Gilbert damping in superconductor/ferromagnet/superconductor junctions.

Sci Adv 2021 Nov 26;7(48):eabh3686. Epub 2021 Nov 26.

International Center for Quantum Materials, School of Physics, Peking University, Beijing 100871, China.

[Figure: see text].
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http://dx.doi.org/10.1126/sciadv.abh3686DOI Listing
November 2021

Evidence for anisotropic spin-triplet Andreev reflection at the 2D van der Waals ferromagnet/superconductor interface.

Nat Commun 2021 Nov 18;12(1):6725. Epub 2021 Nov 18.

International Center for Quantum Materials, School of Physics, Peking University, 100871, Beijing, P. R. China.

Fundamental symmetry breaking and relativistic spin-orbit coupling give rise to fascinating phenomena in quantum materials. Of particular interest are the interfaces between ferromagnets and common s-wave superconductors, where the emergent spin-orbit fields support elusive spin-triplet superconductivity, crucial for superconducting spintronics and topologically-protected Majorana bound states. Here, we report the observation of large magnetoresistances at the interface between a quasi-two-dimensional van der Waals ferromagnet FeTaS and a conventional s-wave superconductor NbN, which provides the possible experimental evidence for the spin-triplet Andreev reflection and induced spin-triplet superconductivity at ferromagnet/superconductor interface arising from Rashba spin-orbit coupling. The temperature, voltage, and interfacial barrier dependences of the magnetoresistance further support the induced spin-triplet superconductivity and spin-triplet Andreev reflection. This discovery, together with the impressive advances in two-dimensional van der Waals ferromagnets, opens an important opportunity to design and probe superconducting interfaces with exotic properties.
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http://dx.doi.org/10.1038/s41467-021-27041-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602320PMC
November 2021

Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma.

J Hepatol 2021 Nov 15. Epub 2021 Nov 15.

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China; Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai 200540, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China. Electronic address:

Background & Aims: To investigate the prognostic value and relevant mechanisms of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA).

Methods: We retrospectively included 962 patients from three cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples.

Results: A quaternary TLS scoring system was established for intra-tumor region (T score) and peri-tumor region (P score) respectively. T score positively correlated with favorable prognosis (P<0.001), whereas a high P score signified a worse survival (P<0.001). Then, mIHC demonstrated that both Tfh and Treg cells were significantly increased in intra-tumor TLSs than peri-tumor counterparts (P<0.05), and Treg cell frequencies within intra-tumor TLSs were positively associated with P score (P<0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into four Immune Classes with distinct prognosis (P<0.001) that differed in the abundance and distribution pattern of TLSs. Patients displayed an immune active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with immune excluded pattern survived at 5 years (P<0.001). The C-index of the Immune Class was statistically higher than the TNM staging system (0.73 vs 0.63, P<0.001). These results were validated in an internal and two external cohorts.

Conclusions: The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. Tfh and Treg cells may play a critical role in determining the functional orientation of spatially different TLSs.

Lay Summary: Tertiary lymphoid structures (TLSs) have been attracting extensive attentions as they are associated with favorable prognosis through activating endogenous anti-tumor immune response. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains elusive. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed opposite prognostic impacts of TLSs located within or outside tumor region. The heterogeneous distribution of Tfh and Treg cells within the spatially different TLSs might be determinant of their functional state. Successfully, the integrated analysis of TLSs stratified iCCAs into four immune subclasses with distinct clinical outcomes.
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http://dx.doi.org/10.1016/j.jhep.2021.10.030DOI Listing
November 2021

The Ci3+3 design for dual-agent combination dose-finding clinical trials.

J Biopharm Stat 2021 Nov 15:1-20. Epub 2021 Nov 15.

Department of Statistics, Colorado State University, Fort Collins, USA.

We propose a rule-based statistical design for combination dose-finding trials with two agents. The Ci3 + 3 design is an extension of the i3 + 3 design with simple up-and-down decision rules comparing the observed toxicity rates and equivalence intervals that define the maximum tolerated dose combination. Ci3 + 3 consists of two stages to allow fast and efficient exploration of the dose-combination space. Statistical inference is restricted to a beta-binomial model for dose evaluation, and the entire design is built upon a set of fixed rules. We show via simulation studies that the Ci3 + 3 design exhibits similar and comparable operating characteristics to more complex designs utilizing model-based inferences. Implementation of Ci3 + 3 for practical trials is simple for the first stage, where the up-and-down decisions may be carried out using a decision table based on the preselected escalation path and i3 + 3. The second stage is not simpler than model-based designs, however, since it also requires computation of posterior probabilities based on a Bayesian model. We believe that the Ci3 + 3 design may provide an alternative choice to help simplify the design and conduct of combination dose-finding trials in practice.
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http://dx.doi.org/10.1080/10543406.2021.1998096DOI Listing
November 2021

Cross-sectional analysis and data-driven forecasting of confirmed COVID-19 cases.

Appl Intell (Dordr) 2021 Jul 5:1-16. Epub 2021 Jul 5.

Onewo Space-Tech Service Co., Ltd., Shenzhen, 518049 China.

The coronavirus disease 2019 (COVID-19) is rapidly becoming one of the leading causes for mortality worldwide. Various models have been built in previous works to study the spread characteristics and trends of the COVID-19 pandemic. Nevertheless, due to the limited information and data source, the understanding of the spread and impact of the COVID-19 pandemic is still restricted. Therefore, within this paper not only daily historical time-series data of COVID-19 have been taken into account during the modeling, but also regional attributes, e.g., geographic and local factors, which may have played an important role on the confirmed COVID-19 cases in certain regions. In this regard, this study then conducts a comprehensive cross-sectional analysis and data-driven forecasting on this pandemic. The critical features, which has the significant influence on the infection rate of COVID-19, is determined by employing XGB (eXtreme Gradient Boosting) algorithm and SHAP (SHapley Additive exPlanation) and the comparison is carried out by utilizing the RF (Random Forest) and LGB (Light Gradient Boosting) models. To forecast the number of confirmed COVID-19 cases more accurately, a Dual-Stage Attention-Based Recurrent Neural Network (DA-RNN) is applied in this paper. This model has better performance than SVR (Support Vector Regression) and the encoder-decoder network on the experimental dataset. And the model performance is evaluated in the light of three statistic metrics, i.e. MAE, RMSE and . Furthermore, this study is expected to serve as meaningful references for the control and prevention of the COVID-19 pandemic.
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http://dx.doi.org/10.1007/s10489-021-02616-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256957PMC
July 2021

UHPLC-MS/MS Method for Quantifying Fangchinoline, Tetrandrine and Calycosin-7-O-β-D-Glucoside of Fangji Huangqi Decoction in Rat Plasma and Its Application to a Pharmacokinetic Study.

J Chromatogr Sci 2021 Nov 4. Epub 2021 Nov 4.

School of Pharmacy, Jilin medical University, 5 Jilin Street, Fengman District, Jilin 132013, China.

Fangji Huangqi Decoction is composed of Stephaniae Tetrandrae Radix, Astragli Radix, Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix Et Rhizoma. It is a classic traditional Chinese medicine formula for the treatment of chronic glomerulonephritis in China. However, its pharmacokinetic characteristics in vivo are still unclear. In this study, a method for quantifying fangchinoline, tetrandrine and calycosin-7-O-β-D-glucoside, the main active constituents of Fangji Huangqi Decoction, in rat plasma by using ultrahigh-performance liquid chromatography-tandem mass spectrometry technique was developed. Plasma samples were processed with a deproteinization procedure using acetonitrile, followed by chromatographic separation on a Shim-pack XR-ODS C18 column using gradient elution of 0.1% aqueous formic acid and acetonitrile at 0.4 mL/min. The analytes and internal standard, diphenhydramine hydrochloride, were detected using positive electrospray ionization in multiple reactions monitoring mode. The optimized mass transition ion-pairs (m/z) were 609.3/367.3 for fangchinoline, 623.3/174.3 for tetrandrine, 447.2/285.1 for calycosin-7-O-β-D-glucoside and 256.2/167.1 for diphenhydramine hydrochloride, respectively. The developed method was validated for intraday and interday precision and accuracy whose values fell in the acceptable limits. Recovery efficiency of all the analytes was found to be >90.5%. Matrix effect was found to be negligible. Stability results showed that the analytes were stable under all conditions. The validated method was successfully used for studying the pharmacokinetics of the three compounds in rat plasma after oral administration of Fangji Huangqi Decoction.
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http://dx.doi.org/10.1093/chromsci/bmab116DOI Listing
November 2021

Reversing the surface charge of MSC-derived small extracellular vesicles by εPL-PEG-DSPE for enhanced osteoarthritis treatment.

J Extracell Vesicles 2021 11;10(13):e12160

Institute of Microsurgery on Extremities, Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) possess a great therapeutical potential for osteoarthritis (OA) treatment. However, the steric and electrostatic hindrance of cartilage matrix leads to very limited distribution of MSC-sEVs in cartilage and low bioavailability of MSC-sEVs after intra-articular injection. To overcome this, a strategy to reverse the surface charge of MSC-sEVs by modifying the MSC-sEVs with a novel cationic amphiphilic macromolecule namely ε-polylysine-polyethylene-distearyl phosphatidylethanolamine (PPD) was developed in this study. Through incubation with 100 μg/ml PPD, positively charged MSC-sEVs (PPD-sEVs) were obtained, and the modification process showed nearly no disturbance to the integrity and contents of sEVs and exhibited good stability under the interference of anionic macromolecules. A more effective cellular uptake and homeostasis modulation ability of PPD-sEVs than unmodified MSC-sEVs to chondrocytes was demonstrated. More importantly, PPD-sEVs demonstrated significantly enhanced cartilage uptake, cartilage penetration, and joint retention capacity as compared to MSC-sEVs. Intra-articular injection of PPD-sEVs into a mouse OA model showed significantly improved bioavailability than MSC-sEVs, which resulted in enhanced therapeutic efficacy with reduced injection frequency. In general, this study provides a facile and effective strategy to improve the intra-articular bioavailability of MSC-sEVs and has a great potential to accelerate the clinical practice of MSC-sEVs based OA therapy.
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http://dx.doi.org/10.1002/jev2.12160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559985PMC
November 2021

Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases.

Acta Neuropathol 2021 12 25;142(6):1003-1023. Epub 2021 Oct 25.

Department of Neurology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Neuronal intranuclear inclusion disease (NIID) is neurodegenerative disease characterized by widespread inclusions. Despite the identification of GGC repeat expansion in 5'UTR of NOTCH2NLC gene in adult-onset NIIDs, its pathogenic mechanism remains unclear. Gain-of-function poly-amino-acid proteins generated by unconventional translation have been revealed in nucleotide repeat expansion disorders, inspiring us to explore the possibility of unconventional translation in NIID. Here we demonstrated that NOTCH2NLC 5'UTR triggers the translation of a polyglycine (polyG)-containing protein, N2NLCpolyG. N2NLCpolyG accumulates in p62-positive inclusions in cultured cells, mouse models, and NIID patient tissues with NOTCH2NLC GGC expansion. Translation of N2NLCpolyG is initiated by an upstream open reading frame (uORF) embedding the GGC repeats. N2NLCpolyG tends to aggregate with the increase of GGC repeat units, and displays phase separation properties. N2NLCpolyG aggregation impairs nuclear lamina and nucleocytoplasmic transport but does not necessarily cause acute death on neuronal cells. Our study suggests a similarity of pathogenic mechanisms between NIID and another GGC-repeat disease, fragile X-associated tremor ataxia syndrome. These findings expand our knowledge of protein gain-of-function in NIID, and further highlight evidence for a novel spectrum of diseases caused by aberrant polyG protein aggregation, namely the polyG diseases.
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http://dx.doi.org/10.1007/s00401-021-02375-3DOI Listing
December 2021

EBV-positive high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study.

Histopathology 2021 Oct 12. Epub 2021 Oct 12.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Aims: It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL).

Methods And Results: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL.

Conclusions: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.
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http://dx.doi.org/10.1111/his.14585DOI Listing
October 2021

3D-cardiomics: A spatial transcriptional atlas of the mammalian heart.

J Mol Cell Cardiol 2021 Oct 5;163:20-32. Epub 2021 Oct 5.

Australian Regenerative Medicine Institute, Monash University, Wellington Road, Clayton, Victoria, Australia; The Jackson Laboratory, Bar Harbor, ME, USA; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne 3052, VIC, Australia; Systems Biology Institute Australia, Clayton, Victoria, Australia. Electronic address:

Understanding the spatial gene expression and regulation in the heart is key to uncovering its developmental and physiological processes, during homeostasis and disease. Numerous techniques exist to gain gene expression and regulation information in organs such as the heart, but few utilize intuitive true-to-life three-dimensional representations to analyze and visualise results. Here we combined transcriptomics with 3D-modelling to interrogate spatial gene expression in the mammalian heart. For this, we microdissected and sequenced transcriptome-wide 18 anatomical sections of the adult mouse heart. Our study has unveiled known and novel genes that display complex spatial expression in the heart sub-compartments. We have also created 3D-cardiomics, an interface for spatial transcriptome analysis and visualization that allows the easy exploration of these data in a 3D model of the heart. 3D-cardiomics is accessible from http://3d-cardiomics.erc.monash.edu/.
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http://dx.doi.org/10.1016/j.yjmcc.2021.09.011DOI Listing
October 2021

Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms.

Biomed Pharmacother 2021 Dec 4;144:112252. Epub 2021 Oct 4.

Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; Engineering Technology Research Center for the Utilization of Functional Components of Organic Natural Products, Dalian University, Dalian 116622, China. Electronic address:

The protein arginine methyltransferase 5 (PRMT5) as the major type II arginine methyltransferase catalyzes the mono- and symmetric dimethylation of arginine residues in both histone and non-histone proteins. Recently, increasing evidence has demonstrated that PRMT5 plays an indispensable role in the occurrence and development of various human cancers by promoting the cell proliferation, invasion, and migration. It has become a promising and valuable target in the cancer epigenetic therapy. This review is to summarize the clinical significance of PRMT5 in the cancers such as lung cancer, breast cancer and colorectal cancer, and the drug discovery targeting PRMT5. Importantly, the existing PRMT5 inhibitors representing different molecular mechanisms, and their pharmacological effect, mechanism of action and biological affinity are analyzed. Clinical status, current problems and future perspective of PRMT5 inhibitors for the treatment of cancers are also discussed, all of which provides crucial help for the future discovery of PRMT5 targeted drugs for cancer treatment.
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http://dx.doi.org/10.1016/j.biopha.2021.112252DOI Listing
December 2021

Nivolumab-associated DRESS in a genetic susceptible individual.

J Immunother Cancer 2021 10;9(10)

Department of Medical Oncology, Zhongshan Hospital Fudan University, Shanghai, China

The use of immune checkpoint inhibitors (ICIs) is rising exponentially in numerous cancers, but immune-related adverse events can occur. We report a rare case of high-grade drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome developed stepwise in a patient with gastric cancer after nivolumab treatment. Subclinical myocarditis was sensitively detected by cardiovascular magnetic resonance 3 weeks after initiating nivolumab. Eruption, eosinophilia, and interstitial pneumonitis occurred 1 week later. Corticosteroids were started and his condition improved. Four months later, when he was still on steroids tapering off, acute kidney injury and sequential herpes zoster virus activation developed. Severe acute tubulointerstitial nephritis (ATN) with an intense infiltration of lymphocytes was observed on renal biopsy. In blood, a substantial shift to Th2 response, an increase of Th17 cells, and strikingly enriched granzyme B and perforin CD8 T cells were detected at ATN onset. Serum interleukin (IL)-5, IL-17, interferon gamma, and IL-6 levels were consistently elevated. Further molecular profiling identified a DRESS risk allele human leukocyte antigen (HLA)-A*31:01 in this patient. His ATN responded favorably to a high dose of corticosteroids. In parallel, complete antitumor response was observed during the clinical course of DRESS. This is the first ever case report of nivolumab-associated DRESS syndrome with exploration of the mechanisms from the histopathological, cellular and molecular aspects. Nivolumab-induced DRESS may result from type IV hypersensitivity-related 'off-target effect' and PD-1 block-mediated 'on-target effect'. HLA risk alleles may constitute the genetic susceptible basis. HLA typing assay has the potential to screen susceptible individuals to avoid ICI-induced DRESS.
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http://dx.doi.org/10.1136/jitc-2021-002879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488716PMC
October 2021

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth.

J Magn Reson Imaging 2021 Sep 24. Epub 2021 Sep 24.

Neurovascular Surgery Program, Department of Neurosurgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.

Background: Cerebral cavernous angioma (CA) is a capillary vasculopathy affecting more than a million Americans with a small fraction of cases demonstrating lesional bleed or growth with major clinical sequelae. Perfusion and permeability are fundamental features of CA pathophysiology, but their role as prognostic biomarkers is unclear.

Purpose: To investigate whether perfusion or permeability lesional descriptors derived from dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging (MRI) can predict subsequent lesional bleed/growth in the year following imaging.

Study Type: Single-site case-controlled study.

Subjects: Two hundred and five consecutively enrolled patients (63.4% female).

Field Strength/sequence: Three-Tesla/T -mapping with contrast-enhanced dynamic two-dimensional (2D) spoiled gradient recalled acquisition (SPGR) sequences.

Assessment: Prognostic associations with bleed/growth (present or absent) in the following year were assessed in 745 CA lesions evaluated by DCEQP in the 205 patients in relation to lesional descriptors calculated from permeability and perfusion maps. A subgroup of 30 cases also underwent peripheral blood collection at the time of DCEQP scans and assays of plasma levels of soluble CD14, IL-1β, VEGF, and soluble ROBO4 proteins, whose weighted combination had been previously reported in association with future CA bleeding.

Statistical Tests: Mann-Whitney U-test for univariate analyses. Logistic regression models minimizing the Bayesian information criterion (BIC), testing sensitivity and specificity (receiver operating characteristic curves) of weighted combinations of parameters.

Results: The best prognostic biomarker for lesional bleed or growth included brainstem lesion location, mean lesional permeability, and low-value perfusion cluster mean (BIC = 201.5, sensitivity = 77%, specificity = 72%, P < 0.05). Adding a previously published prognostic plasma protein biomarker improved the performance of the imaging model (sensitivity = 100%, specificity = 88%, P < 0.05).

Data Conclusion: A combination of MRI-based descriptors reflecting higher lesional permeability and lower perfusion cluster may potentially predict future bleed/growth in CAs. The sensitivity and specificity of the prognostic imaging biomarker can be enhanced when combined with brainstem lesion location and a plasma protein biomarker of CA hemorrhage.

Level Of Evidence: 2 TECHNICAL EFFICACY: Stage 5.
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http://dx.doi.org/10.1002/jmri.27935DOI Listing
September 2021

Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing.

Mol Neurodegener 2021 Sep 22;16(1):66. Epub 2021 Sep 22.

Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.

Background: Aberrant alternative splicing plays critical role in aging and age-related diseases. Heterogeneous nuclear ribonucleoproteins (hnRNPs) reportedly regulate RNA splicing process. Whether and how hnRNPs contribute to age-related neurodegenerative diseases, especially Alzheimer's disease (AD), remain elusive.

Methods: Immunoblotting and immunostaining were performed to determine expression patterns and cellular/subcellular localization of the long isoform of hnRNP D-like (L-DL), which is a hnRNP family member, in mouse hippocampus. Downregulation of L-DL in WT mice was achieved by AAV-mediated shRNA delivery, followed by memory-related behavioural tests. L-DL interactome was analysed by affinity-precipitation and mass spectrometry. Alternative RNA splicing was measured by RNA-seq and analyzed by bioinformatics-based approaches. Downregulation and upregulation of L-DL in APP/PS1 mice were performed using AAV-mediated transduction.

Results: We show that L-DL is specifically localized to nuclear speckles. L-DL levels are decreased in the hippocampus of aged mouse brains and downregulation of L-DL impairs cognition in mice. L-DL serves as a structural component to recruit other speckle proteins, and regulates cytoskeleton- and synapse-related gene expression by altering RNA splicing. Mechanistically, these splicing changes are modulated via L-DL-mediated interaction of SF3B3, a core component of U2 snRNP, and U2AF65, a U2 spliceosome protein that guides U2 snRNP's binding to RNA. In addition, L-DL levels are decreased in APP/PS1 mouse brains. While downregulation of L-DL deteriorates memory deficits and overexpression of L-DL improves cognitive function in AD mice, by regulating the alternative splicing and expression of synaptic gene CAMKV.

Conclusions: Our findings define a molecular mechanism by which hnRNP L-DL regulates alternative RNA splicing, and establish a direct role for L-DL in AD-related synaptic dysfunction and memory decline.
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http://dx.doi.org/10.1186/s13024-021-00485-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456587PMC
September 2021

Gender congruence and mental health problems among Chinese transgender and gender non-conforming individuals: A process model involving rumination and stigma consciousness.

J Clin Psychol 2021 Sep 16. Epub 2021 Sep 16.

Department of Psychology, Faculty of Social Sciences, University of Macau, Macau, China.

Objective: The present study examined the roles of gender identity rumination and stigma consciousness in the relationship between gender congruence (comfort with one's gender identity and external appearance) and mental health problems (anxiety and depression).

Methods: Three hundred and fourteen Chinese individuals identified as transgender and gender non-conforming (TGNC) individuals were recruited through the Internet and answered an online questionnaire (M  = 24.34 years, standard deviation = 5.80).

Results: Gender congruence was associated with anxiety and depression through three indirect pathways: rumination, stigma consciousness, and sequentially through rumination and stigma consciousness.

Conclusion: Gender congruence is an intrapersonal resource that reduces mental health problems through its positive impacts on the TGNC identity process. A more consistent feeling of gender, a lower level of rumination, and a reduced level of consciousness about stigma could be potential working points for interventions in the TGNC community to help alleviate their mental health problems.
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http://dx.doi.org/10.1002/jclp.23248DOI Listing
September 2021

High Counts of CD68+ and CD163+ Macrophages in Mantle Cell Lymphoma Are Associated With Inferior Prognosis.

Front Oncol 2021 30;11:701492. Epub 2021 Aug 30.

Department of Pathology, Yale University School of Medicine, New Haven, CT, United States.

Background: Lymphoma-associated macrophages (LAMs) are key components in the lymphoma microenvironment, which may impact disease progression and response to therapy. There are two major subtypes of LAMs, CD68+ M1 and CD163+ M2. M2 LAMs can be transformed from M1 LAMs, particularly in certain diffuse large B-cell lymphomas (DLBCL). While mantle cell lymphoma (MCL) is well-known to contain frequent epithelioid macrophages, LAM characterization within MCL has not been fully described. Herein we evaluate the immunophenotypic subclassification, the expression of immune checkpoint molecule PD-L1, and the prognostic impact of LAMs in MCL.

Materials And Methods: A total of 82 MCL cases were collected and a tissue microarray block was constructed. Immunohistochemical staining was performed using CD68 and CD163, and the positive cells were recorded manually in four representative 400× fields for each case. Multiplexed quantitative immunofluorescence assays were carried out to determine PD-L1 expression on CD68+ M1 LAMs and CD163+ M2 LAMs. In addition, we assessed Ki67 proliferation rate of MCL by an automated method using the QuPath digital imaging analysis. The cut-off points of optimal separation of overall survival (OS) were analyzed using the X-Tile software, the SPSS version 26 was used to construct survival curves, and the log-rank test was performed to calculate the -values.

Results: MCL had a much higher count of M1 LAMs than M2 LAMs with a CD68:CD163 ratio of 3:1. Both M1 and M2 LAMs were increased in MCL cases with high Ki67 proliferation rates (>30%), in contrast to those with low Ki67 (<30%). Increased number of M1 or M2 LAMs in MCL was associated with an inferior OS. Moreover, high expression of PD-L1 on M1 LAMs had a slightly better OS than the cases with low PD-L1 expression, whereas low expression of PD-L1 on M2 LAMs had a slightly improved OS, although both were not statistically significant.

Conclusions: In contrast to DLBCL, MCL had a significantly lower rate of M1 to M2 polarization, and the high levels of M1 and M2 LAMs were associated with poor OS. Furthermore, differential PD-L1 expressions on LAMs may partially explain the different functions of tumor-suppressing or tumor-promoting of M1 and M2 LAMs, respectively.
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http://dx.doi.org/10.3389/fonc.2021.701492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435777PMC
August 2021

Incorporating external data into the analysis of clinical trials via Bayesian additive regression trees.

Stat Med 2021 Dec 7;40(28):6421-6442. Epub 2021 Sep 7.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

Most clinical trials involve the comparison of a new treatment to a control arm (eg, the standard of care) and the estimation of a treatment effect. External data, including historical clinical trial data and real-world observational data, are commonly available for the control arm. With proper statistical adjustments, borrowing information from external data can potentially reduce the mean squared errors of treatment effect estimates and increase the power of detecting a meaningful treatment effect. In this article, we propose to use Bayesian additive regression trees (BART) for incorporating external data into the analysis of clinical trials, with a specific goal of estimating the conditional or population average treatment effect. BART naturally adjusts for patient-level covariates and captures potentially heterogeneous treatment effects across different data sources, achieving flexible borrowing. Simulation studies demonstrate that BART maintains desirable and robust performance across a variety of scenarios and compares favorably to alternatives. We illustrate the proposed method with an acupuncture trial and a colorectal cancer trial.
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http://dx.doi.org/10.1002/sim.9191DOI Listing
December 2021

Monophosphoryl lipid A directly regulates Th1 cytokine production in human CD4 T-cells through Toll-like receptor 2 and 4.

Immunobiology 2021 09 30;226(5):152132. Epub 2021 Aug 30.

Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen 518060, China; School of Medicine, Shenzhen University, Shenzhen, China; Third Affiliated Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, China. Electronic address:

Background: The monophosphoryl lipid A (MPLA) is a detoxified LPS derivative and an emerging safe immune adjuvant in human vaccine development. The adjuvant MPLA promotes antigen-presenting cell (APC) function and preferentially induces a Th1 response following vaccination. However, the mechanism by which the MPLA detoxicates and exerts its adjuvants effect on T-cell, particualrly the Th1 response is unknown.

Aims: We assessed the direct effects of MPLA on murine and human CD4 T-cell proliferation and the profile of cytokine production ex vivo.

Results: We report that CD4 T-cells only express functional TLR2 and TLR4 when activated by TCR stimulation, in particularly in the presence of IFNα. The activated T cells thereafter can respond directly to MPLA. MPLA does not affect T-cell proliferation in human T cells, but can induce a balanced Th1 cytokine profile in CD4 T-cells by reducing the production of Th1 cytokines and enhancing the production of the regulatory cytokine IL-10. The MPLA-mediated regulatory effect on activated CD4 T-cells is TLR2 and TLR4 dependent and can be abolished by the lipid A blocker polymyxin B.

Conclusion: These data provide evidence, at least in part, for the safe induction of an appropriate level of Th1 response by adjuvant MPLA in human vaccine development.
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http://dx.doi.org/10.1016/j.imbio.2021.152132DOI Listing
September 2021

Staging Chronic Hepatitis B Related Liver Fibrosis with a Fractional Order Calculus Diffusion Model.

Acad Radiol 2021 Aug 22. Epub 2021 Aug 22.

Central Research Institute, United Imaging Healthcare, Shanghai, China.

Rationale And Objectives: Accurately staging liver fibrosis is of great clinical significance. We aimed to evaluate the clinical potential of the non-Gaussian fractional order calculus (FROC) diffusion model in staging liver fibrosis.

Materials And Methods: A total of 82 patients with chronic hepatitis B (CHB) were included in this prospective study. Diffusion weighted imaging (DWI)-derived parameters including the diffusion coefficient (D), fractional order parameter (β) and microstructural quantity (μ) sourced from FROC-DWI, and apparent diffusion coefficient (ADC) derived from mono-exponential DWI, as well as the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) were calculated. Their correlations with fibrosis stages and the diagnostic efficacy in predicting liver fibrosis were assessed and compared.

Results: D (r = -0.667), β (r = -0.671), μ (r = -0.481), and ADC (r = -0.665) displayed significant correlations with fibrosis stages (p < 0.001). D, β and ADC (p < 0.01) were independently associated with fibrosis; and compared to inflammatory activity, fibrosis was the independent factor significantly correlated with D, β and ADC (p < 0.001). There were no significant differences between the area under curves of D, β, μ or their combinations and ADC for predicting different fibrosis stages (p > 0.05). The diagnostic performance of the combined index with four diffusion metrics was better than D, β, μ or ADC used alone (p < 0.05) as well as APRI or FIB-4 (p < 0.01) in fibrosis staging.

Conclusion: FROC-DWI was valuable in staging liver fibrosis in patients with CHB, but there were no significant differences between the FROC-DWI parameters and the classical ADC. However, the combined DWI-derived index including D, β, μ and ADC offered the best diagnostic efficacy and may serve as a reliable tool for fibrosis evaluation, superior to APRI and FIB-4.
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http://dx.doi.org/10.1016/j.acra.2021.07.005DOI Listing
August 2021

URI1 suppresses irradiation-induced reactive oxygen species (ROS) by activating autophagy in hepatocellular carcinoma cells.

Int J Biol Sci 2021 22;17(12):3091-3103. Epub 2021 Jul 22.

Department of Cell Biology, Institute of Bioengineering, School of Medicine, Soochow University, Suzhou 215123, China.

Radiotherapy has been extensively applied in cancer treatment. However, this treatment is ineffective in Hepatocellular carcinoma (HCC) due to lack of radiosensitivity. Unconventional prefoldin RPB5 interactor 1 (URI1) exhibits characteristics similar to those oncoproteins, which promotes survival of cancer cells. As a consequence of the irradiation, the levels of endogenous reactive oxygen species (ROS) rise. In the current study, we analyzed the role of URI1 in the control of ROS levels in HepG2 cells. Upon URI1 overexpression, HepG2 cells significantly suppressed irradiation-induced ROS, which may help cells escape from oxidative toxicity. And our data demonstrated that overexpression of URI1 not only resulted in an increase of autophagic flux, but also resulted in an further increased capacity of autophagy to eliminate ROS. It indicated that URI1 suppressed irradiation-induced ROS through activating autophagy. Moreover, URI1 activated autophagy by promoting the activities of AMP-activated protein kinase (AMPK). Results showed that overexpression of URI1 increased the phosphorylation of AMPKα at the Thr172 residue and the activated-AMPK promoted the phosphorylation of forkhead box O3 (FOXO3) at the Ser253 residue, which significantly induced autophagy. Taken together, our findings provide a mechanism that URI1 suppresses irradiation-induced ROS by activating autophagy through AMPK/FOXO3 signaling pathway. These new molecular insights will provide an important contribution to our better understanding about irradiation insensitivity of HCC.
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http://dx.doi.org/10.7150/ijbs.55689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375238PMC
July 2021

Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations.

Liver Cancer 2021 Jul 30;10(4):320-329. Epub 2021 Mar 30.

Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported.

Methods: Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated.

Results: Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4-8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8-15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence.

Conclusions: Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.
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http://dx.doi.org/10.1159/000514313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339461PMC
July 2021

Highly sensitive time-resolved fluoroimmunoassay for the quantitative onsite detection of Alternaria longipes in tobacco.

J Appl Microbiol 2021 Jul 27. Epub 2021 Jul 27.

China National Tobacco Quality Supervision and Test Center, Zhengzhou, China.

Aims: Alternaria longipes is a causal agent of brown spot of tobacco, which remains a serious threat to tobacco production. Herein, we established a detection method for A. longipes in tobacco samples based on the principle of time-resolved fluoroimmunoassay, in order to fulfil the requirement of rapid, sensitive and accurate detection in situ.

Methods And Results: A monoclonal antibody against A. longipes was generated, and its purity and titration were assessed using western blot and ELISA. The size of europium (III) nanospheres was measured to confirm successful antibody conjugation. The method described here can detect A. longipes protein lysates as low as 0.78 ng ml , with recovery rates ranging from 85.96% to 99.67% in spiked tobacco. The specificity was also confirmed using a panel of microorganisms.

Conclusions: The fluorescent strips allow rapid and sensitive onsite detection of A. longipes in tobacco samples, with high accuracy, specificity, and repeatability.

Significance And Impact Of The Study: This novel detection method provides convenience of using crude samples without complex procedures, and therefore allows rapid onsite detection by end users and quick responses towards A. longipes, which is critical for disease control and elimination of phytopathogens.
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http://dx.doi.org/10.1111/jam.15233DOI Listing
July 2021

Reactive Intralymphovascular Immunoblastic Proliferations Mimicking Aggressive Lymphomas.

Am J Surg Pathol 2021 Jul 26. Epub 2021 Jul 26.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center, Houston, TX Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA Department of Pathology, Advent Health-Orlando, Orlando, FL Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Reactive intralymphovascular immunoblastic proliferations (ILVIPs) may mimic aggressive lymphomas and are rarely reported. Herein, we characterize the clinicopathologic features of 8 patients with ILVIPs. No patients had lymphadenopathy, hepatosplenomegaly, or other findings suggestive of lymphoma. The ILVIPs involved the small or large intestine (n=5) and appendix (n=3). Patients were evaluated for abdominal pain, suspected appendicitis, intestinal obstruction, diverticulitis, volvulus, or tumor resection. Histologic sections showed expanded lymphovascular spaces filled by intermediate to large immunoblasts, positive for CD38, CD43, CD45, CD79a, and MUM1/IRF4 in all cases tested. Five of 6 (83%) cases were positive for CD30. CD20 was weakly positive in a subset of cells in 2 (25%) cases, and PAX5 was weakly positive in 4 (50%) cases. The immunoblasts expressed polytypic light chains in all cases tested. In 1 case, a subset of immunoblasts expressed T-cell markers indicating the presence of a T-cell component. The immunoblasts were negative for ALK, BCL-2, BCL-6, CD10, CD56, CD138, and Epstein-Barr virus-encoded small RNA in all cases assessed. The proliferation index shown by Ki-67 was high with a median of 80%. In all 6 cases tested, the immunoblasts were shown within lymphatic channels highlighted by D2-40. In conclusion, ILVIPs can be rarely observed in patients with inflammatory or infectious conditions, especially in gastrointestinal tract surgical specimens. The immunoblasts are predominantly of B-lineage with a postgerminal center immunophenotype and are located within lymphatic channels. It is essential to distinguish reactive ILVIPs from aggressive lymphomas to avoid unnecessary therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001785DOI Listing
July 2021

Flow Cytometric Evaluation of Surface and Cytoplasmic TRBC1 Expression in the Differential Diagnosis of Immature T-Cell Proliferations.

Am J Clin Pathol 2021 Jul 24. Epub 2021 Jul 24.

Division of Hematopathology, Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.

Objectives: Flow cytometric detection of T-cell clonality is challenging, particularly in differential diagnosis of immature T-cell proliferations. Studies have shown utility of TRBC1, in conjunction with other T-cell markers, as reliable means to identify T-cell clonality by flow cytometry. One limitation of surface TRBC1 (sTRBC1) evaluation is it cannot be detected in surface CD3 (sCD3)-negative T cells, such as normal or abnormal immature T-cell precursors. Here, we assess surface and cytoplasmic TRBC1 expression patterns in the differential diagnosis of T-lymphoblastic leukemia/lymphoma (T-ALL) vs normal thymocyte expansions.

Methods: Forty-three samples containing T-ALL, thymoma, normal thymus, and/or indolent T-lymphoblastic proliferation (i-TLBP), were evaluated.

Results: All 24 cases with normal thymocytes or i-TLBPs revealed a characteristic and reproducible sCD3/sTRBC1 expression pattern indicative of polytypic T-cell maturation. In contrast, all 19 T-ALLs lacked this polytypic maturation pattern and were either completely negative for sCD3/sTRBC1 or showed a minor sCD3-positive subset with a monotypic TRBC1 expression pattern. Cytoplasmic TRBC1 evaluation in 9 T-ALLs demonstrated a monotypic intracellular TRBC1-positive (n = 4) or TRBC1-negative (n = 5) expression, indicative of clonality.

Conclusions: Our findings demonstrate flow cytometric evaluation of surface and cytoplasmic TRBC1 expression can aid detection of T-cell clonality and differential diagnosis of immature T-cell proliferations.
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http://dx.doi.org/10.1093/ajcp/aqab098DOI Listing
July 2021

Tumor size and perineural invasion predict outcome of gastric high-grade neuroendocrine neoplasms.

Endocr Connect 2021 Aug 13;10(8):947-954. Epub 2021 Aug 13.

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

A new subcategory, grade 3 neuroendocrine tumors, is incorporated into the grading system of pancreatic neuroendocrine neoplasms in the 2017 WHO classification in order to differentiate grade 3 neuroendocrine tumors from neuroendocrine carcinomas. The 2019 WHO classification extends the concept of grade 3 neuroendocrine tumors to gastrointestinal high-grade neuroendocrine neoplasms. However, there is still limited study focusing on the gastric grade 3 neuroendocrine tumors and gastric neuroendocrine carcinomas. We retrospectively enrolled 151 gastric high-grade neuroendocrine neoplasms patients, who underwent radical resection from January 2007 to December 2015. Clinicopathologic and prognostic features were studied. The Surveillance, Epidemiology, and End Results (SEER) database was used to verify the prognostic determinants found in the Zhongshan cohort. Neuroendocrine carcinomas showed a higher Ki67 index and higher mitotic count than grade 3 neuroendocrine tumors. We identified 109 (72.2%) patients with neuroendocrine carcinomas, 12 (7.9%) patients with grade 3 neuroendocrine tumors, and 30 (19.9%) patients with mixed neuroendocrine-non-neuroendocrine neoplasms. Although neuroendocrine carcinomas demonstrated higher Ki67 index (P = 0.004) and mitoses (P = 0.001) than grade 3 neuroendocrine tumors, their prognosis after radical resection did not demonstrate significant differences (P = 0.709). Tumor size, perineural invasion, and TNM stage were independent prognostic factors of gastric high-grade neuroendocrine neoplasms.
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http://dx.doi.org/10.1530/EC-21-0017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428078PMC
August 2021

The utility of a myeloid mutation panel for the diagnosis of myelodysplastic syndrome and myelodysplastic/myeloproliferative neoplasm.

Int J Lab Hematol 2021 Dec 16;43(6):1501-1509. Epub 2021 Jul 16.

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.

Introduction: The diagnosis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is based on morphology and cytogenetics/FISH findings per 2017 WHO classification. With rare exceptions, somatic mutations have not been incorporated as the diagnostic criteria.

Methods: We analyzed the utility of mutational analysis with a targeted 54-gene or 40-gene next-generation sequencing (NGS) panel in the diagnosis of MDS and MDS/MPN.

Results: We retrospectively collected 92 patients who presented with unexplained cytopenia with or without cytosis, including 32 low-grade MDS (MDS-L), 18 high-grade MDS (MDS-H), 5 therapy-related MDS (MDS-TR), 19 MDS/MPN, and 18 negative cases. Of 92 patients, 197 somatic mutations involving 38 genes were detected and had variant allele frequency (VAF) ranging from 3% to 99%. The most common mutated genes were TET2, ASXL1, RUNX1, TP53, SRSF2, and SF3B1. MDS-L, MDS-H, MDS-TR, and MDS/MPN showed an average number of somatic mutations with a mean VAF of 1.9/33%, 2.6/30%, 2/36%, and 4/41%, respectively. SF3B1 mutations were exclusively observed in MDS-L and MDS/MPN. TP53 gene mutations were more frequently seen in MDS-H and MDS-TR. Among 34 patients with a diagnosis of MDS or MDS/MPN with normal cytogenetics, 31 patients (91%) had at least 1 mutation and 24 patients (71%) had ≥2 mutations with ≥10% VAF.

Conclusion: A myeloid mutational panel provides additional evidence of clonality besides cytogenetics/FISH studies in the diagnosis of cytopenia with or without cytosis. Two or more mutations with ≥10% VAF highly predicts MDS and MDS/MPN with a positive predictive value of 100%.
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http://dx.doi.org/10.1111/ijlh.13659DOI Listing
December 2021

MicroRNA-21 mediates the protective role of emulsified isoflurane against myocardial ischemia/reperfusion injury in mice by targeting SPP1.

Authors:
Ji Yuan Xiaoyang Fu

Cell Signal 2021 Oct 10;86:110086. Epub 2021 Jul 10.

School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China; People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China; Department of Vascular, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China. Electronic address:

Isoflurane has demonstrated to exert protective impacts against ischemia/reperfusion (I/R) injury in some organs. This research explored the role of emulsified isoflurane (EI) in myocardial I/R injury through the interaction with microRNA-21 (miR-21). The myocardial I/R injury mouse models established by coronary artery ligation were respectively treated with EI, miR-21 mimic/inhibitor or silenced secreted phosphoprotein 1 (SPP1) plasmids. Then, the pathology, fibrosis and cardiomyocyte apoptosis in mouse myocardial tissues were observed. Furthermore, the expression levels of miR-21, SPP1, oxidative stress indices, inflammatory factors and apoptotic proteins in mouse myocardial tissues were determined. The targeting relation between miR-21 and SPP1 was confirmed. MiR-21 was poorly expressed and SPP1 was highly expressed in myocardial I/R injury mice. EI treatment, elevated miR-21, or silenced SPP1 improved cardiac function and suppressed the oxidative stress, myocardial fibrosis, inflammatory reaction and cardiomyocyte apoptosis in myocardial I/R injury mice, thereby reliving the myocardial I/R injury. These therapeutic effects of EI were repressed by miR-21 inhibition. Additionally, SPP1 was targeted by miR-21. Results in our research indicated that miR-21 mediated the therapeutic effect of EI on myocardial I/R injury in mice by targeting SPP1. This study may provide a novel treatment strategy for myocardial I/R injury.
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http://dx.doi.org/10.1016/j.cellsig.2021.110086DOI Listing
October 2021

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Nat Commun 2021 07 2;12(1):4091. Epub 2021 Jul 2.

Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People's Republic of China.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
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http://dx.doi.org/10.1038/s41467-021-24386-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253833PMC
July 2021

KLF5/LINC00346/miR‑148a‑3p axis regulates inflammation and endothelial cell injury in atherosclerosis.

Int J Mol Med 2021 Aug 24;48(2). Epub 2021 Jun 24.

Department of Cardiovascular Disease, Changzhou No. 2 People's Hospital, Affiliated Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China.

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases, which are related to high morbidity and mortality rates. The present study aimed to investigate the role of the Krüppel‑like factor 5 (KLF5)/LINC00346/miR‑148a‑3p loop in AS. The expression levels of KLF5 in serum and of KLF5/LINC00346/miR‑148a‑3p in human umbilical vein endothelial cells (HUVECs) were detected by RT‑qPCR analysis. The protein expression levels of KLF5, phosphorylated (p‑)endothelial nitric oxide synthase (eNOS) and eNOS in HUVECs were analyzed by western blot analysis. Changes in the levels of TNF‑α, IL‑1β, IL‑6 and nitric oxide (NO) were determined in the supernatant through the application of available commercial kits. The binding of KLF5 to the promoter region of LINC00346 was verified by chromatin immunoprecipitation (ChIP)‑PCR assay. The combinatory interaction between KLF5 and LINC00346, LINC00346 and miR‑148a‑3p, and miR‑148a‑3p and KLF5 was confirmed by luciferase reporter assay. The results revealed that KLF5 expression was increased in the serum of patients with AS and also in oxidized low‑density lipoprotein (OX‑LDL)‑stimulated HUVECs. The transcription factor KLF5 promoted the transcription of LINC00346. KLF5 interference or LINC00346 interference inhibited the expression of inflammatory factors and functional injury in OX‑LDL‑stimulated HUVECs. LINC00346 functioned as a sponge of miR‑148a‑3p. miR‑148a‑3p overexpression inhibited the expression of inflammatory factors and functional injury in OX‑LDL‑stimulated HUVECs and miR‑148a‑3p targeted KLF5 expression. On the whole, the present study demonstrates that KLF5 interference induces the downregulation of LINC00346 and also inhibits inflammation and functional injury in OX OX‑LDL‑stimulated HUVECs by upregulating miR‑148a‑3p expression.
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http://dx.doi.org/10.3892/ijmm.2021.4985DOI Listing
August 2021

An Individualized Contrast-Enhanced Liver Computed Tomography Imaging Protocol Based on Body Mass Index in 126 Patients Seen for Liver Cirrhosis.

Med Sci Monit 2021 Jun 24;27:e932109. Epub 2021 Jun 24.

Department of Radiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China (mainland).

BACKGROUND Computed tomography (CT) imaging using iodinated contrast medium is associated with the radiation dose to the patient, which may require reduction in individual circumstances. This study aimed to evaluate an individualized liver CT protocol based on body mass index (BMI) in 126 patients investigated for liver cirrhosis. MATERIAL AND METHODS From November 2017 to December 2020, in this prospective study, 126 patients with known or suspected liver cirrhosis were recruited. Patients underwent liver CT using individualized protocols based on BMI, as follows. BMI ≤24.0 kg/m²: 80 kV, 352 mg I/kg; BMI 24.1-28.0 kg/m²: 100 kV, 440 mg I/kg; BMI ≥28.1 kg/m²: 120 kV, 550 mg I/kg. Figure of merit (FOM) and size-specific dose estimates (SSDEs) were calculated and compared using the Mann-Whitney U test. Subjective image quality and timing adequacy of the late arterial phase were evaluated with Likert scales. RESULTS The SSDE was significantly lower in the 80 kV protocol, corresponding to a dose reduction of 36% and 50% compared with the others (all P<0.001). In the comparison of 80-, 100-, and 120-kV protocols, no statistically significant differences were found in FOMs (P=0.108~0.620). Of all the examinations, 95.2% (120 of 126) were considered as appropriate timing for the late arterial phase. In addition, overall image quality, hepatocellular carcinoma conspicuity, and detection rate did not differ significantly among the 3 protocols (P=0.383~0.737). CONCLUSIONS This study demonstrated the feasibility of using an individualized liver CT protocol based on BMI, and showed that patients with lower BMI should receive lower doses of iodinated contrast medium and significantly reduced radiation dose.
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http://dx.doi.org/10.12659/MSM.932109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240488PMC
June 2021
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