Publications by authors named "Limin Zheng"

142 Publications

Case Report: Ruptured Middle Cerebral Artery Aneurysm With Intrasylvian Hematoma Successfully Treated by Coil Embolization and Minimally Invasive Puncture and Drainage.

Front Neurol 2021 21;12:646990. Epub 2021 Jun 21.

Department of Neurosurgery, Taian Central Hospital, Taian, China.

Up to one-third (12-35%) of patients with aneurysmal subarachnoid hemorrhage experience intracerebral hematoma. Ruptured middle cerebral artery (MCA) aneurysm with hematoma is usually accompanied by progressive cerebral swelling with poor outcomes; however, it can be successfully treated by coil embolization and minimally invasive puncture and drainage. From February 2012 to March 2019, six surgeries for ruptured MCA aneurysms with intrasylvian hematoma were performed at our clinic. All patients had intracranial hematomas of <30 ml and GCS scores >8. The patients were treated by coil embolization and minimally invasive puncture and drainage. The aneurysms in all patients were completely embolized and the hematomas were mostly removed by minimally invasive puncture. The Glasgow outcome scale (GOS) scores of all patients were more than 4 at discharge when they discharged. Coil embolization and minimally invasive puncture and drainage are viable treatments for ruptured MCA aneurysms with hematomas, especially if the patient is too old, in a complicated state to undergo craniotomy, is unwilling to undergo craniotomy, or is at a greater risk of bleeding 3 days after surgery.
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http://dx.doi.org/10.3389/fneur.2021.646990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256150PMC
June 2021

Replication-dependent biogenesis of turnip crinkle virus long noncoding RNAs.

J Virol 2021 Jun 23:JVI0016921. Epub 2021 Jun 23.

Department of Plant Pathology, Ohio Agricultural Research and Development Center, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691.

Long noncoding RNAs (lncRNAs) of virus origin accumulate in cells infected by many positive strand (+) RNA viruses to bolster viral infectivity. Their biogenesis mostly utilizes exoribonucleases of host cells that degrade viral genomic or subgenomic RNAs in the 5'-to-3' direction until being stalled by well-defined RNA structures. Here we report a viral lncRNA that is produced by a novel replication-dependent mechanism. This lncRNA corresponds to the last 283 nucleotides of the turnip crinkle virus (TCV) genome, hence is designated tiny TCV subgenomic RNA (ttsgR). ttsgR accumulated to high levels in TCV-infected cells when the TCV-encoded RNA-dependent RNA polymerase (RdRp), also known as p88, was overexpressed. Both (+) and (-) strand forms of ttsgR were produced in a manner dependent on the RdRp functionality. Strikingly, templates as short as ttsgR itself were sufficient to program ttsgR amplification, as long as the TCV-encoded replication proteins, p28 and p88, were provided . Consistent with its replicational origin, ttsgR accumulation required a 5' terminal carmovirus consensus sequence (CCS), a sequence motif shared by genomic and subgenomic RNAs of many viruses phylogenetically related to TCV. More importantly, introducing a new CCS motif elsewhere in the TCV genome was alone sufficient to cause the emergence of another lncRNA. Finally, abolishing ttsgR by mutating its 5' CCS gave rise to a TCV mutant that failed to compete with wildtype TCV in Arabidopsis. Collectively our results unveil a replication-dependent mechanism for the biogenesis of viral lncRNAs, thus suggesting that multiple mechanisms, individually or in combination, may be responsible for viral lncRNA production. Many positive strand (+) RNA viruses produce long noncoding RNAs (lncRNAs) during the process of cellular infections, and mobilize these lncRNAs to counteract antiviral defenses, as well as coordinate the translation of viral proteins. Most viral lncRNAs arise from 5'-to-3' degradation of longer viral RNAs being stalled at stable secondary structures. We report a viral lncRNA that is produced by the replication machinery of turnip crinkle virus (TCV). This lncRNA, designated ttsgR, shares the terminal characteristics with TCV genomic and subgenomic RNAs, and over-accumulates in the presence of moderately overexpressed TCV RNA-dependent RNA polymerase (RdRp). Furthermore, templates that are of similar sizes as ttsgR itself are readily replicated by TCV replication proteins (p28 and RdRp) provided from non-viral sources. In summary, this study establishes an approach for uncovering low abundance viral lncRNAs, and characterizes a replicating TCV lncRNA. Similar investigations on human-pathogenic (+) RNA viruses could yield novel therapeutic targets.
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http://dx.doi.org/10.1128/JVI.00169-21DOI Listing
June 2021

High S100A9 cell density predicts a poor prognosis in hepatocellular carcinoma patients after curative resection.

Aging (Albany NY) 2021 06 22;13(12):16367-16380. Epub 2021 Jun 22.

MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.

S100A9 is differentially expressed in various cell types and is associated with the development, progression and metastasis of various cancers. However, the expression, distribution, and clinical significance of S100A9 in hepatocellular carcinoma (HCC) remain unclear. In the present study, The Cancer Genome Atlas (TCGA) database was used to examine gene expression in HCC; we found that expression was associated with HCC prognosis. In addition, S100A9 protein expression was assessed by immunohistochemistry analysis of tissues from 382 HCC patients. We found that the infiltration of S100A9 cells in both tumor and nontumor tissues could predict poor overall survival ( = 0.0329, tumor; = 0.0003, nontumor) and a high recurrence risk ( = 0.0387, tumor; = 0.0015, nontumor) in our tissue microarray analysis. Furthermore, immunofluorescence double staining revealed that the primary S100A9-expressing cells in adjacent nontumoral tissue were CD15 neutrophils, and both CD68 macrophages and CD15 neutrophils expressed S100A9 in HCC tumor tissues. Taken together, the results suggest that high S100A9 cell density predicts a poor prognosis in HCC patients, and S100A9 expression could potentially serve as an independent prognostic marker for HCC.
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http://dx.doi.org/10.18632/aging.203162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266308PMC
June 2021

Extract of spores induces cell cycle arrest of hepatoma cell via endoplasmic reticulum stress.

Pharm Biol 2021 Dec;59(1):704-714

MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Context: Zhao, Xu et Zhang (Ganodermataceae) has been used for the prevention or treatment of a variety of diseases, including cancer.

Objective: We investigated the antitumor activity and mechanism of an extract from against hepatocellular carcinoma.

Materials And Methods: A extract (GSE) was obtained from sporoderm-broken spores by supercritical fluid carbon dioxide extraction. Hepatoma cells, HepG2 cells, were treated with emulsified sample of GSE at 12.5, 25, 50, 100 and 150 μg/mL for 24 h. The Alamar Blue assay was used to examine growth inhibitory effects. Changes in cell structure and morphology were assessed via transmission electron microscopy and confocal laser scanning microscope. Cell cycle distribution was analysed by flow cytometry.

Results: GSE suppressed the proliferation of HepG2 cells (IC=70.14 μg/mL). Extensive cytoplasmic vacuolation originating from dilation of the endoplasmic reticulum (ER) was shown in GSE-treated HepG2 cells. GSE treatment also upregulated the expression of ER stress-related proteins in HepG2 cells. Cells tended to be arrested at the G2/M cell cycle stage after GSE treatment (30.8 ± 1.4% and 42.2 ± 2.6% at GSE with 50 μg/mL and 100 μg/mL vs. 21.03 ± 1.10%, control). Pre-treatment with salubrinal, an inhibitor of ER stress, effectively attenuated cell cycle arrest induced by GSE.

Discussion And Conclusions: Our findings provide new evidence that GSE suppresses growth of cancer cells through activating the ER stress pathway. The GSE may be clinically applied in the prevention and/or treatment of cancer.
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http://dx.doi.org/10.1080/13880209.2021.1931354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205061PMC
December 2021

A structure-dependent ratiometric fluorescence sensor based on metal-organic framework for detection of 2,6-pyridinedicarboxylic acid.

Anal Bioanal Chem 2021 Jul 19;413(16):4227-4236. Epub 2021 May 19.

Department of Analytical Chemistry, China Pharmaceutical University, Nanjing, 211198, China.

In the present work, a structure-dependent ratiometric fluorescence (RF) sensor constructed with boric acid-modified carbon quantum dots (B-CQDs) and Tb-MOF(MOF-76) was developed for sensing 2,6-pyridinedicarboxylic acid (DPA). Based on the distinct fluorescent responses of B-CQDs and MOF-76 to DPA, MOF-76/B-CQDs can be developed as a RF sensor for DPA detection. In this RF sensor, the reticulated cross-linked structure of MOF-76/B-CQDs can be destroyed by DPA due to a strong coordination effect between DPA and the Tb of MOF-76, resulting in the quenching of the fluorescence of B-CQD and the restoration of the fluorescence of MOF-76 after the addition of DPA. Benefiting from the confinement effect of the special structure change, the presented sensor showed high sensitivity toward DPA with a detection limit of 3.05 μM and excellent selectivity over the monochromatic fluorescence sensor.
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http://dx.doi.org/10.1007/s00216-021-03369-6DOI Listing
July 2021

Dual and opposing roles of the androgen receptor in VETC-dependent and invasion-dependent metastasis of hepatocellular carcinoma.

J Hepatol 2021 May 15. Epub 2021 May 15.

Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China; MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P.R. China. Electronic address:

Background & Aims: Contradictory roles of the androgen receptor (AR) in hepatocellular carcinoma (HCC) metastasis have been reported. We have shown that VETC (vessels encapsulating tumor clusters) mediates invasion-independent metastasis, whereas VETC HCCs metastasize in an invasion-dependent manner. Here we aimed to reveal the roles of AR in HCC metastasis.

Methods: Mouse xenograft models, clinical samples, and cell models were used.

Results: AR expression was significantly lower in HCCs with VETC pattern, portal vein tumor thrombus, endothelium-coated microemboli or high recurrence rates. Overexpressing AR in VETC hepatoma cells suppressed VETC formation and intrahepatic metastasis but promoted pulmonary metastasis of mouse xenografts. AR decreased the transcription of Angiopoietin-2 (Angpt2), a factor essential for VETC formation, by binding to the Angpt2 promoter. The roles of AR in inhibiting VETC formation and intrahepatic metastasis were attenuated by restoring Angpt2 expression, suggesting that AR may repress VETC-dependent intrahepatic metastasis by inhibiting Angpt2 expression and VETC formation. On the other hand, AR upregulated Rac1 expression, promoted lamellipodia formation and increased cell migration/invasion. A Rac1 inhibitor abrogated the AR-mediated promotion of migration/invasion and pulmonary metastasis of VETC hepatoma cells, but did not affect the AR-mediated inhibition of intrahepatic metastasis. Furthermore, an AR inhibitor decreased Rac1 expression and attenuated both intrahepatic and pulmonary metastasis of VETC xenografts, and this effect was abrogated by restoring Rac1 expression. These data indicate that AR may facilitate the lung metastasis of VETC HCCs and both the liver/lung metastases of VETC HCCs by upregulating Rac1 expression and then promoting migration/invasion.

Conclusion: AR plays dual and opposing roles in VETC-dependent and invasion-dependent metastasis, which highlights the complex functions of AR and the importance of individualized cancer therapy.

Lay Summary: This study revealed the dual and opposing roles of AR in VETC-dependent and invasion-dependent metastasis and elucidated the underlying mechanisms, which provided novel insights into the complex regulatory network of AR in HCC metastasis and may have important implications for precision medicine.
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http://dx.doi.org/10.1016/j.jhep.2021.04.053DOI Listing
May 2021

Optimized Intracellular Staining Reveals Heterogeneous Cytokine Production Ability of Murine and Human Hematopoietic Stem and Progenitor Cells.

Front Immunol 2021 14;12:654094. Epub 2021 Apr 14.

MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China.

Under stress conditions, hematopoietic stem and progenitor cells (HSPCs) can translate danger signals into a plethora of cytokine signals. These cytokines, or more precisely their combination, instruct HSPCs to modify the magnitude and composition of hematopoietic output in response to the threat, but investigations into the heterogeneous cytokine expression and regulatory mechanisms are hampered by the technical difficulty of measuring cytokine levels in HSPCs at the single-cell level. Here, we optimized a flow cytometry-based method for the simultaneous assessment of multiple intracellular cytokines in HSPCs. By selecting an optimal combination of cytokine restimulation reagents, protein transport inhibitors, and culture supplements, an optimized restimulation protocol for intracellular staining was developed. Using this method, we successfully examined expression levels of granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in murine and human HSPC subsets under steady-state or different stress conditions. Different cytokine expression patterns were observed, suggesting distinct regulatory modes of cytokine production dependent on the HSPC subset, cytokine, disease, organ, and species. Collectively, this technical advance may help to obtain a better understanding of the nature of HSPC heterogeneity on the basis of differential cytokine production.
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http://dx.doi.org/10.3389/fimmu.2021.654094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079767PMC
April 2021

Comparative evaluation of the bispectral index (BIS) and BISpro during propofol anaesthesia.

J Int Med Res 2021 Apr;49(4):3000605211001705

Department of Anaesthesiology, Peking University Shenzhen Hospital, Shenzhen, China.

Objective: To compare the accuracy, correlation and agreement between the bispectral index (BIS) and BISpro during propofol anaesthesia.

Methods: The BIS, BISpro, heart rate, target-concentration of propofol and Observer's Assessment of Alertness and Sedation (OAA/S) score were recorded every 30 s in female patients scheduled for hysteroscopic surgery. Propofol anaesthesia was induced by an initial target-controlled concentration (1.0 μg/ml) followed by a stepwise increase (0.5 μg/ml) until the patient was unresponsive. Spearman's correlation coefficient and prediction probability were calculated for the association between sedation levels and the above parameters. The ability of investigated parameters to distinguish between OAA/S scores was analysed. Bland-Altman analysis was used to compare the agreement between BIS and BISpro. The BIS and BISpro cut-off values for lost response were also determined.

Results: Out of 30 patients in total, a high correlation was found between BIS and BISpro, and both correlated well with OAA/S score. Only BIS was able to distinguish all investigated OAA/S states accurately, but the ability to predict OAA/S score 5 to loss of response was comparable between BIS and BISpro. The calculated cut-off values were 68 for BIS and 70 for BISpro.

Conclusion: BISpro and BIS are reliable monitors of general anaesthesia during sedation.: Chinese Clinical Trial Registry (URL: www.chictr.org.cn): ChiCTR1900024037 (retrospectively registered).
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http://dx.doi.org/10.1177/03000605211001705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047833PMC
April 2021

Icaritin Induces Anti-tumor Immune Responses in Hepatocellular Carcinoma by Inhibiting Splenic Myeloid-Derived Suppressor Cell Generation.

Front Immunol 2021 26;12:609295. Epub 2021 Feb 26.

Ministry of Education Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Recent studies have demonstrated that splenic extramedullary hematopoiesis (EMH) is an important mechanism for the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissues, and thus contributes to disease progression. Icaritin, a prenylflavonoid derivative from plants of the genus, has been implicated as a novel immune-modulator that could prolong the survival of hepatocellular carcinoma (HCC) patients. However, it is unclear whether icaritin achieves its anti-tumor effects via the regulation of MDSCs generated by EMH in HCC. Here, we investigated the anti-tumor potential of icaritin and its mechanism of action in murine HCC. Icaritin suppressed tumor progression and significantly prolonged the survival of mice-bearing orthotopic and subcutaneous HCC tumors. Rather than exerting direct cytotoxic activity against tumor cells, icaritin significantly reduced the accumulation and activation of tumoral and splenic MDSCs, and increased the number and activity of cytotoxic T cells. Mechanistically, icaritin downregulates the tumor-associated splenic EMH, thereby reducing the generation and activation of MDSCs. The inhibitory effects of icaritin on human MDSCs were verified in short-term culture with cord-blood derived hematopoietic precursors. Furthermore, icaritin synergistically enhanced the therapeutic efficacy of immune checkpoint blockade therapy in HCC mice. These findings revealed that icaritin dampens tumoral immunosuppression to elicit anti-tumor immune responses by preventing MDSC generation via the attenuation of EMH. Thus, icaritin may serve as a novel adjuvant or even a stand-alone therapeutic agent for the effective treatment of HCC.
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http://dx.doi.org/10.3389/fimmu.2021.609295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952329PMC
July 2021

Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF.

Front Immunol 2020 2;11:616367. Epub 2021 Feb 2.

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

Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.
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http://dx.doi.org/10.3389/fimmu.2020.616367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884351PMC
June 2021

The Gene Can Regulate the Fecundity of the Green Peach Aphid, (Sulzer).

Front Physiol 2020 12;11:596392. Epub 2021 Jan 12.

College of Plant Protection, Hunan Agricultural University, Changsha, China.

(Sulzer), commonly known as the green peach aphid, is a notorious pest that causes substantial losses to a range of crops and can transmit several plant viruses, including potato virus Y (PVY). Chemical insecticides provide only partial control of this pest and their use is not environmentally sustainable. In recent years, many genes related to growth, development, and reproduction have been used as targets for pest control. These include (), a highly conserved gene that has been reported to play an essential part in the genesis of germline cells and, hence, in fecundity in the model insect . We hypothesized that the () gene was a potential target that could be used to regulate the population. In this study, we report the first investigation of an ortholog of in , designated , and describe its role in the fecundity of this insect. First, we identified the mRNA sequence in the transcriptome database, verified its identity with reverse transcription-polymerase chain reaction (RT-PCR), and then evaluated the transcription levels of in nymphs of different instars and tissues with real-time quantitative PCR (RT-qPCR). To investigate its role in regulating the fecundity of , we used RNA interference (RNAi) to silence the expression of in adult insects; this resulted in a significant reduction in the number of embryos (50.6%, < 0.01) and newborn nymphs (55.7%, < 0.01) in the treated aphids compared with controls. Interestingly, was also significantly downregulated in aphids fed on tobacco plants that had been pre-infected with PVY , concomitant with a significant reduction (34.1%, < 0.01) in fecundity. Collectively, these data highlight the important role of in regulating fecundity in and indicate that is a promising RNAi target gene for control of this pest species.
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http://dx.doi.org/10.3389/fphys.2020.596392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835840PMC
January 2021

Tomato Chlorosis Virus Infection Facilitates MED Reproduction by Elevating Expression.

Insects 2021 Jan 25;12(2). Epub 2021 Jan 25.

Department of Entomology, University of Kentucky, Lexington, KY 40546, USA.

Transmission of plant pathogenic viruses mostly relies on insect vectors. Plant virus could enhance its transmission by modulating the vector. Previously, we showed that feeding on virus infected plants can promote the reproduction of the sweet potato whitefly, MED (Q biotype). In this study, using a whitefly-Tomato chlorosis virus (ToCV)-tomato system, we investigated how ToCV modulates MED reproduction to facilitate its spread. Here, we hypothesized that ToCV-infected tomato plants would increase MED fecundity via elevated gene expression. As a result, fecundity and the relative expression of MED was measured on ToCV-infected and uninfected tomato plants on days 4, 8, 12, 16, 20 and 24. The role of on MED reproduction was examined in the presence and absence of ToCV using dietary RNAi. ToCV infection significantly increased MED fecundity on days 12, 16 and 20, and elevated expression on days 8, 12 and 16. Both ovarian development and fecundity of MED were suppressed when was silenced with or without ToCV infection. These combined results suggest that ToCV infection increases MED fecundity via elevated expression.
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http://dx.doi.org/10.3390/insects12020101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911321PMC
January 2021

Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer.

Signal Transduct Target Ther 2021 Jan 8;6(1). Epub 2021 Jan 8.

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

Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are shaped in response to anti-PD-1 treatment and what their impact on therapeutic efficacy is in colorectal cancer (CRC). In this study, the levels of infiltrating MDSCs were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment. A negative correlation between T-cell activation and MDSC function was also observed in fresh human CRC tissues. Mechanistic studies revealed that autocrine IFN-α/β upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL-DR5 interaction and acted synergistically with TNF-α to inhibit MDSC function of suppressing the T-cell response through the JNK-NMDAR-ARG-1 pathway. Moreover, blockade of IFN-α/β and TNF-α abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infiltrating MDSCs in a CRC mouse model. This result suggested that reprogramming MDSCs by IFN-α/β and TNF-α from activated T cells was necessary for successful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy.
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http://dx.doi.org/10.1038/s41392-020-00377-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791142PMC
January 2021

Bottleneck, Isolate, Amplify, Select (BIAS) as a mechanistic framework for intracellular population dynamics of positive-sense RNA viruses.

Virus Evol 2020 Jul 12;6(2):veaa086. Epub 2020 Nov 12.

Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki-aoba, Aoba-ku, Sendai 980-0845, Japan.

Many positive-sense RNA viruses, especially those infecting plants, are known to experience stringent, stochastic population bottlenecks inside the cells they invade, but exactly how and why these populations become bottlenecked are unclear. A model proposed ten years ago advocates that such bottlenecks are evolutionarily favored because they cause the isolation of individual viral variants in separate cells. Such isolation in turn allows the viral variants to manifest the phenotypic differences they encode. Recently published observations lend mechanistic support to this model and prompt us to refine the model with novel molecular details. The refined model, designated Bottleneck, Isolate, Amplify, Select (BIAS), postulates that these viruses impose population bottlenecks on themselves by encoding bottleneck-enforcing proteins (BNEPs) that function in a concentration-dependent manner. In cells simultaneously invaded by numerous virions of the same virus, BNEPs reach the bottleneck-ready concentration sufficiently early to arrest nearly all internalized viral genomes. As a result, very few (as few as one) viral genomes stochastically escape to initiate reproduction. Repetition of this process in successively infected cells isolates viral genomes with different mutations in separate cells. This isolation prevents mutant viruses encoding defective viral proteins from hitchhiking on sister genome-encoded products, leading to the swift purging of such mutants. Importantly, genome isolation also ensures viral genomes harboring beneficial mutations accrue the cognate benefit exclusively to themselves, leading to the fixation of such beneficial mutations. Further interrogation of the BIAS hypothesis promises to deepen our understanding of virus evolution and inspire new solutions to virus disease mitigation.
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http://dx.doi.org/10.1093/ve/veaa086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733609PMC
July 2020

The AC2 Protein of a Bipartite Geminivirus Stimulates the Transcription of the BV1 Gene through Abscisic Acid Responsive Promoter Elements.

Viruses 2020 12 7;12(12). Epub 2020 Dec 7.

Department of Plant Pathology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.

Geminiviruses possess single-stranded, circular DNA genomes and control the transcription of their late genes, including BV1 of many bipartite begomoviruses, through transcriptional activation by the early expressing AC2 protein. DNA binding by AC2 is not sequence-specific; hence, the specificity of AC2 activation is thought to be conferred by plant transcription factors (TFs) recruited by AC2 in infected cells. However, the exact TFs AC2 recruits are not known for most viruses. Here, we report a systematic examination of the BV1 promoter (P) of the mungbean yellow mosaic virus (MYMV) for conserved promoter motifs. We found that MYMV P contains three abscisic acid (ABA)-responsive elements (ABREs) within its first 70 nucleotides. Deleting these ABREs, or mutating them all via site-directed mutagenesis, abolished the capacity of P to respond to AC2-mediated transcriptional activation. Furthermore, ABRE and other related ABA-responsive elements were prevalent in more than a dozen Old World begomoviruses we inspected. Together, these findings suggest that ABA-responsive TFs may be recruited by AC2 to BV1 promoters of these viruses to confer specificity to AC2 activation. These observations are expected to guide the search for the actual TF(s), furthering our understanding of the mechanisms of AC2 action.
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http://dx.doi.org/10.3390/v12121403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762296PMC
December 2020

Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer.

Cancer Immunol Res 2021 01 11;9(1):20-33. Epub 2020 Nov 11.

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

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism-related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an model, generating MDSCs from CD34 myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1-expressing myeloid cells and increased CD8 and granzyme B T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0389DOI Listing
January 2021

Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma.

J Hepatol 2021 Mar 31;74(3):627-637. Epub 2020 Oct 31.

Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China; MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P. R. China. Electronic address:

Background & Aims: Macrophages (Mϕ) represent a major component of tumor tissues and play an important role in both tumor progression and therapeutic response. Although tumor Mϕ are generally considered to be derived from circulating monocytes, emerging evidence indicates that tissue Mϕ pools can be maintained by self-renewal. We aimed to elucidate the contribution, phenotype, and regulatory mechanisms of proliferating Mϕ in human hepatocellular carcinoma (HCC).

Methods: Flow cytometry analyses were performed to examine the presence and phenotype of proliferating Mϕ in fresh HCC tissues. Dual immunofluorescence staining was applied to analyze the prognostic value of proliferating Mϕ. The underlying regulatory mechanisms were examined using human monocyte-derived Mϕ.

Results: Tumor-infiltrating Mϕ exhibited a significantly higher proliferative capacity than Mϕ in non-tumor tissues. A higher level of Mϕ proliferation was positively correlated with Mϕ density in the tumor and a poor prognosis in patients with HCC. Proliferating Mϕ were less differentiated (with increased CD206 expression) and were induced by the tumor cell-derived soluble small molecule, adenosine, but not proteins, lipids, or large peptides. Mechanistic studies demonstrated that autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) released by tumor-stimulated Mϕ could enhance A2A receptor expression on Mϕ and function synergistically with adenosine to elicit Mϕ proliferation in HCC.

Conclusions: Local Mϕ proliferation is an important mechanism for Mϕ accumulation in HCC tissues. Tumor-derived adenosine functions synergistically with autocrine GM-CSF released from activated Mϕ, which promotes Mϕ proliferation. Thus, selective modulation of Mϕ accumulation at the source may provide a novel strategy for cancer therapy.

Lay Summary: Tumor-associated macrophages (TAMs) have been reported to play an essential role in both tumor progression and therapeutic response. A fundamental understanding of the mechanisms that regulate macrophage accumulation in tumors will undoubtedly lead to the development of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.
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http://dx.doi.org/10.1016/j.jhep.2020.10.021DOI Listing
March 2021

A cross-sectional study on diabetes epidemiology among people aged 40 years and above in Shenyang, China.

Sci Rep 2020 10 20;10(1):17742. Epub 2020 Oct 20.

Department of Neurology, Jin Qiu Hospital of Liaoning Province, Geriatric Hospital of Liaoning Province, Shenyang, 110000, Liaoning, China.

This study aimed at understanding the diabetic prevalence, awareness, treatment and control rates and their influencing factors among people aged ≥ 40 years in Shenyang, China. A face-to-face cross-sectional epidemiological survey was conducted on the respondents using the national unified questionnaire. A total of 3922 respondents were enrolled, including 609 cases of diabetes. The diabetic prevalence rate was 15.5%, and was higher in rural areas than that in urban areas (17.7% vs. 14.2%, p = 0.004), while no difference was observed between men and women (14.8% vs. 16.1%, p = 0.242). Advanced age, hypertension and dyslipidemia were the diabetes influencing factors. Among the 609 respondents with diabetes, the diabetic awareness and treatment rates, and the control rate of fasting plasma glucose were 82.3%, 36.6% and 17.1%, respectively. In different age groups, the diabetic awareness rate was higher in men than that in women, and the treatment rate was higher in women than that in men. The diabetic patients, who consumed fruit for ≥ 5 days a week, accounted for 16.3%, and their diabetic treatment (28.1%) and control rates (44.1%) were lower. Shenyang people aged ≥ 40 years have higher diabetic prevalence and awareness rates, and lower diabetic treatment and control rates. Finally, it is necessary to enhance awareness and education about diabetes, to improve its treatment and control rates.
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http://dx.doi.org/10.1038/s41598-020-74889-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576584PMC
October 2020

Immune landscape and therapeutic strategies: new insights into PD-L1 in tumors.

Cell Mol Life Sci 2021 Feb 17;78(3):867-887. Epub 2020 Sep 17.

The Fifth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

PD-1/PD-L1 axis represents an important target for renormalizing and resetting anti-tumor immunity in cancer patients. Currently, anti-PD-1/PD-L1 therapy has been applied in a broad spectrum of tumors and has yielded durable remission in patients. However, how to further broaden the application, guide personalized therapeutic strategies, and improve clinical responses remains a vital task. At present, PD-L1 expression is an important parameter of clinical indications for immune checkpoint blockade in many types of cancers, a strategy based on the supposition that positive PD-L1 expression reflects local T cell response. Recent studies have revealed that PD-L1 expression is regulated by multiple layers of complicated factors, during which the host immune microenvironment exerts a pivotal role and determines the clinical efficacy of the therapy. In this review, we will summarize recent findings on PD-1/PD-L1 in cancer, focusing on how local immune landscape participates in the regulation of PD-L1 expression and modification. Importantly, we will also discuss these topics in the context of clinical treatment and analyze how these fundamental principles might inspire our efforts to develop more precise and effective immune therapeutics for cancer.
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http://dx.doi.org/10.1007/s00018-020-03637-1DOI Listing
February 2021

B cells polarize pathogenic inflammatory T helper subsets through ICOSL-dependent glycolysis.

Sci Adv 2020 Sep 9;6(37). Epub 2020 Sep 9.

MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China.

B cells constitute abundant cellular components in inflamed human tissues, but their role in pathogenesis of inflammatory T helper (T) subsets is still unclear. Here, we demonstrate that B cells, particularly resting naïve B cells, have a previously unrecognized helper function that is involved in shaping the metabolic process and subsequent inflammatory differentiation of T-cell receptor-primed T cells. ICOS/ICOSL axis-mediated glucose incorporation and utilization were crucial for inflammatory T subset induction by B cells, and activation of mTOR was critical for T cell glycolysis in this process. Consistently, upon encountering ICOSL B cells, activated effector memory T cells from patients with rheumatoid arthritis or systemic lupus erythematosus spontaneously differentiated into inflammatory T subsets. Immunotherapy using rituximab that specifically depleted B cells in patients with rheumatoid arthritis efficiently abrogated the capabilities of memory T cells to incorporate and use glucose, thereby impairing the pathogenic differentiation of inflammatory T subsets.
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http://dx.doi.org/10.1126/sciadv.abb6296DOI Listing
September 2020

Icaritin-induced immunomodulatory efficacy in advanced hepatitis B virus-related hepatocellular carcinoma: Immunodynamic biomarkers and overall survival.

Cancer Sci 2020 Nov 24;111(11):4218-4231. Epub 2020 Sep 24.

National Cancer Center/National Clinical Research Center, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Advanced hepatitis B virus (HBV)-related hepatocellular carcinoma HCC with poor prognosis is often associated with chronic inflammation, immune tolerance, and marked heterogeneity. The interleukin-6 (IL-6)/JAK/STAT3 signal pathways play multiple regulatory roles in modulating inflammation and immunity in cancers. Polarization of myeloid-derived suppressor cells (MDSCs) is involved in HBV-related immunosuppression and CD8 T-cell activation through ERK/IL-6/STAT3. Icaritin is a small molecule that has displayed anticancer activities through IL-6/JAK/STAT3 pathways in tumor cells and immune cells including CD8 T cells, MDSCs, neutrophils, and macrophages. This study aimed to confirm icaritin immunomodulation in advanced HBV-related HCC patients with poor prognosis. Immunomodulation of MDSCs was evaluated in BALB/c mice in vivo. Immunomodulation of serum cytokines and a panel of immune checkpoint proteins were assessed in HBV-related, histologically confirmed HCC patients. Poor prognostic characteristics included HBV infection, bulky tumors, Child-Pugh B classification, and metastasis. Clinical end-points included safety, tumor response, and overall survival (OS). Icaritin treatment-induced dynamics of serum cytokines IL-6, IL-8, IL-10, and tumor necrosis factor-α, and soluble immune checkpoint proteins TIM3, LAG3, CD28, CD80, and CTLA-4 were assessed. No grade III/IV treatment-related adverse events were observed. Time-to-progression was significantly associated with the prognostic factors. Improved survival was observed in the advanced HCC patients with dynamic changes of cytokines, immune checkpoint proteins, and immune cells. Median OS (329-565 days) was significantly correlated with baseline hepatitis B surface antigen positivity, cytokines, tumor neoantigens, and Stenotrophomonas maltophilia infection. Composite biomarker scores of high-level α-fetoprotein and T helper type I (Th1)/Th2 cytokines associated with favorable survival warrant further clinical development of icaritin as an alternative immune-modulatory regimen to treat advanced HCC patients with poor prognosis.
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http://dx.doi.org/10.1111/cas.14641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648021PMC
November 2020

CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity.

Cell Mol Immunol 2021 Aug 15;18(8):1934-1944. Epub 2020 Jul 15.

Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, China.

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca influx and membrane potential (V)-induced Ca influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.
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http://dx.doi.org/10.1038/s41423-020-0499-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322328PMC
August 2021

Generation of Myeloid Cells in Cancer: The Spleen Matters.

Front Immunol 2020 5;11:1126. Epub 2020 Jun 5.

MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.

Myeloid cells are key components of the tumor microenvironment and critical regulators of disease progression. These innate immune cells are usually short-lived and require constant replenishment. Emerging evidence indicates that tumors alter the host hematopoietic system and induce the biased differentiation of myeloid cells to tip the balance of the systemic immune activities toward tumor-promoting functions. Altered myelopoiesis is not restricted to the bone marrow and also occurs in extramedullary organs. In this review, we outline the recent advances in the field of cancer-associated myelopoiesis, with a focus on the spleen, the major site of extramedullary hematopoiesis in the cancer setting. We discuss the functional specialization, distinct mechanisms, and clinical relevance of cancer-associated myeloid cell generation from early progenitors in the spleen and its potential as a novel therapeutic target.
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http://dx.doi.org/10.3389/fimmu.2020.01126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291604PMC
April 2021

Myeloid signature reveals immune contexture and predicts the prognosis of hepatocellular carcinoma.

J Clin Invest 2020 09;130(9):4679-4693

MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences.

BACKGROUNDDespite an increasing appreciation of the roles that myeloid cells play in tumor progression and therapy, challenges remain in interpreting the tumor-associated myeloid response balance and its translational value. We aimed to construct a simple and reliable myeloid signature for hepatocellular carcinoma (HCC).METHODSUsing in situ immunohistochemistry, we assessed the distribution of major myeloid subtypes in both peri- and intratumoral regions of HCC. A 2-feature-based, myeloid-specific prognostic signature, named the myeloid response score (MRS), was constructed using an L1-penalized Cox regression model based on data from a training subset (n = 244), a test subset (n = 244), and an independent internal (n = 341) and 2 external (n = 94; n = 254) cohorts.RESULTSThe MRS and the MRS-based nomograms displayed remarkable discriminatory power, accuracy, and clinical usefulness for predicting recurrence and patient survival, superior to current staging algorithms. Moreover, an increase in MRS was associated with a shift in the myeloid response balance from antitumor to protumor activities, accompanied by enhanced CD8+ T cell exhaustion patterns. Additionally, we provide evidence that the MRS was associated with the efficacy of sorafenib treatment for recurrent HCC.CONCLUSIONWe identified and validated a simple myeloid signature for HCC that showed remarkable prognostic potential and may serve as a basis for the stratification of HCC immune subtypes.FUNDINGThis work was supported by the National Science and Technology Major Project of China, the National Natural Science Foundation of China, the Science and Information Technology of Guangzhou, the Fundamental Research Funds for the Central Universities, the Guangdong Basic and Applied Basic Research Foundation, and the China Postdoctoral Science Foundation.
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http://dx.doi.org/10.1172/JCI135048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456226PMC
September 2020

Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma.

J Hepatol 2020 10 12;73(4):906-917. Epub 2020 May 12.

MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China. Electronic address:

Background & Aims: Neutrophils are one of the most abundant components in human hepatocellular carcinoma (HCC) and have been shown to play important roles in regulating disease progression. However, neutrophils are very short-lived cells in circulation, and mechanisms regulating their accumulation and functions in HCC are not yet fully understood.

Methods: Monocytes were purified from non-tumor or paired tumor tissues of patients with HCC, and their production of neutrophil-attracting chemokines was evaluated. Mechanisms regulating the expression of CXCL2/8 by tumor monocytes, and the role of tumor monocyte-derived chemokines and cytokines in modulating neutrophil accumulation and functions were studied with both ex vivo analyses and in vitro experiments.

Results: Monocyte-derived CXCL2 and CXCL8 were major factors in regulating the recruitment of neutrophils into tumor milieus. These chemokines, in addition to tumor-derived soluble factors, could inhibit apoptosis and sustain survival of neutrophils, thus leading to neutrophil accumulation in tumor tissues. Moreover, monocyte-derived TNF-α acted synergistically with tumor-derived soluble factors to induce the production of the pro-metastasis factor OSM by neutrophils. Further, the glycolytic switch in tumor-infiltrating monocytes mediated their production of CXCL2 and CXCL8 via the PFKFB3-NF-κB signaling pathway. Accordingly, levels of PFKFB3, CXCL2/CXCL8 production in monocytes and infiltration of OSM-producing neutrophils were positively correlated in human HCC tissues.

Conclusions: Our results unveiled a previously unappreciated link between monocytes and neutrophils in human HCC, identifying possible targets that could be therapeutically exploited in the future.

Lay Summary: Neutrophils constitute a major but poorly understood component of human hepatocellular carcinoma (HCC). Herein, we unveil a novel mechanism by which metabolic switching in monocytes promotes the accumulation of neutrophils in the tumors of patients with HCC. Both monocyte-produced chemokines and signals from the tumor microenvironment promote the production of the pro-metastatic factor OSM by neutrophils. These data identify potential targets for immune-based anticancer therapies for HCC.
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http://dx.doi.org/10.1016/j.jhep.2020.05.004DOI Listing
October 2020

Rh(i)-Catalyzed enantioselective and scalable [4 + 2] cycloaddition of 1,3-dienes with dialkyl acetylenedicarboxylates.

Org Biomol Chem 2020 04;18(15):2956-2961

School of Science, Harbin Institute of Technology, Shenzhen, 518055, China.

An asymmetric intermolecular [4 + 2] cycloaddition of 1,3-dienes with dialkyl acetylenedicarboxylates, which was catalyzed by a rhodium(i)-chiral phosphoramidite complex, was developed. This protocol provided a highly enantioselective access to prepare carbonyl substituted cyclohexa-1,4-dienes with up to 96% yield and >99% ee. Notably, a cycloaddition on the 10 g scale gave the product in 92% yield and with 99% ee, which showed great potential for the scale-up synthesis of carbonyl substituted cyclohexa-1,4-dienes. In addition, oxidative aromatizations and hydrolysis of the products were also investigated.
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http://dx.doi.org/10.1039/d0ob00361aDOI Listing
April 2020

Translation-Independent Roles of RNA Secondary Structures within the Replication Protein Coding Region of Turnip Crinkle Virus.

Viruses 2020 03 22;12(3). Epub 2020 Mar 22.

Department of Plant Pathology, The Ohio State University, Wooster, OH 44691, USA.

RNA secondary structures play diverse roles in positive-sense (+) RNA virus infections, but those located with the replication protein coding sequence can be difficult to investigate. Structures that regulate the translation of replication proteins pose particular challenges, as their potential involvement in post-translational steps cannot be easily discerned independent of their roles in regulating translation. In the current study, we attempted to overcome these difficulties by providing viral replication proteins in . Specifically, we modified the plant-infecting turnip crinkle virus (TCV) into variants that are unable to translate one (p88) or both (p28 and p88) replication proteins, and complemented their replication with the corresponding replication protein(s) produced from separate, non-replicating constructs. This approach permitted us to re-examine the p28/p88 coding region for potential RNA elements needed for TCV replication. We found that, while more than a third of the p88 coding sequence could be deleted without substantially affecting viral RNA levels, two relatively small regions, known as RSE and IRE, were essential for robust accumulation of TCV genomic RNA, but not subgenomic RNAs. In particular, the RSE element, found previously to be required for regulating the translational read-through of p28 stop codon to produce p88, contained sub-elements needed for efficient replication of the TCV genome. Application of this new approach in other viruses could reveal novel RNA secondary structures vital for viral multiplication.
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http://dx.doi.org/10.3390/v12030350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150753PMC
March 2020

Higher Ramie mosaic virus transmission efficiency by females than by males of Bemisia tabaci MED.

Sci Rep 2020 01 16;10(1):525. Epub 2020 Jan 16.

Plant Protection college, Hunan Agricultural University, No 1 Nongda Road, Furong District, Changsha, 410120, Hunan province, P.R. China.

Begomoviruses can modify their transmission vector, Bemisia tabaci, to benefit their spread, although this may not always be the case. Here, the new begomovirus Ramie mosaic virus (RaMoV) and its vector B. tabaci MED, which is dominant in China and many regions of the world, were used as a model to examine direct and indirect interaction and virus transmission by B. tabaci MED of different sexes. No significant direct or indirect effects of RaMoV were observed in B. tabaci MED females, although RaMoV could shorten the life span of B. tabaci MED females by up to 4 days. A test of RaMoV transmission by different sexes of B. tabaci MED showed that there was higher virus transmission efficiency by females than males. Overall, RaMoV is transmitted by B. tabaci MED in a sex-dependent manner, and further research is needed to uncover the mechanism of the difference in RaMoV transmission by different sexes of B. tabaci.
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http://dx.doi.org/10.1038/s41598-019-57343-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965624PMC
January 2020

Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma.

Hepatol Int 2020 Jan 4;14(1):80-95. Epub 2019 Dec 4.

MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, Guangdong, China.

Background: Sorafenib is the most widely used first-line treatment for patients with advanced hepatocellular carcinoma (HCC), but such treatment provides only limited survival benefits that might be related to the immune status of distinct tumor microenvironments. A fundamental understanding of the distribution and phenotypes of T lymphocytes in tumors will undoubtedly lead to the development of novel immunotherapeutic strategies that could possibly enhance the efficacy of sorafenib treatments.

Methods: Flow cytometry, immunohistochemistry and immunofluorescence analyses were performed to detect the infiltration and distribution of various leukocyte populations, and the expression of different immune checkpoint molecules in fresh HCC tumor tissues. Correlations among indicating genes were calculated in 365 patients with HCC from The Cancer Genome Atlas (TCGA) data set, and the cumulative overall survival time was calculated using the Kaplan-Meier method. Moreover, role of adenosinergic pathway on sorafenib anti-tumor efficacy was investigated using both subcutaneous and orthotopic transplantation tumor model in immune competent C57BL/6 mice.

Results: We revealed that levels of CD3 and CD8 T cells were significantly downregulated in HCC tumor tissue, so were the infiltration of CD169 cells (a Mφ subpopulation with T cell activation capacities) and their contact with CD8 cells in tumor milieus. Moreover, levels of PD-1 and CD39 expression were significantly upregulated in human HCC-infiltrating CD4 and CD8 T cells, and CD39CD8 T cells exhibited a CD69PD-1perforinIFNγ "exhausted" phenotype. Levels of both CD39 T cells infiltration and adenosine receptor ADORA2B expression in tumor tissues were negatively correlated with overall survival of patients with HCC. Accordingly, mice treated with sorafenib in combination with adenosine A receptor blockage reagents exhibited significantly reduced tumor progression compared with control groups.

Conclusions: These results suggest that adenosinergic pathway might represent an applicable target for sorafenib-combined-therapies in human HCC.
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http://dx.doi.org/10.1007/s12072-019-10003-2DOI Listing
January 2020

EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma.

J Immunother Cancer 2019 11 14;7(1):300. Epub 2019 Nov 14.

Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.

Background: Accumulating studies suggest that targeting epigenetic modifications could improve the efficacy of tumor immunotherapy; however, the mechanisms underlying this phenomenon remain largely unknown. Here, we investigated the ability of the epigenetic modifier, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), to regulate the expression of immune checkpoint inhibitor, programmed death-1 ligand 1 (PD-L1) in hepatocellular carcinoma (HCC).

Methods: Immunohistochemistry and multiplex immunofluorescence staining were performed to analyze the expression and correlation of EZH2 and PD-L1 in HCC tissues. Immunoblotting, quantitative real-time PCR, flow cytometry, chromatin immunoprecipitation, and dual-luciferase reporter gene assays were performed to evaluate the regulatory roles of EZH2 on PD-L1 expression.

Results: In vitro cell experiments revealed that EZH2 negatively regulated the PD-L1 expression of hepatoma cell lines in IFNγ-dependent manner. Mechanistic studies demonstrated that EZH2 could suppress PD-L1 expression by upregulating the H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and interferon regulatory factor 1 (IRF1), an essential transcription factor for PD-L1 expression, without affecting the activation of the IFNγ-signal transducer and activator of transcription 1 (STAT1) pathway. Clinical samples from HCC patients with immune-activated microenvironments showed negative correlations between EZH2 and PD-L1 expression in hepatoma cells. Multivariate Cox analysis demonstrated that the combination of EZH2 and PD-L1 was an independent prognostic factor for both OS and RFS for patients with HCC.

Conclusions: The epigenetic modificator EZH2 can suppress the expression of immune checkpoint inhibitor PD-L1 by directly upregulating the promoter H3K27me3 levels of CD274 and IRF1 in hepatoma cells, and might serve as a potential therapeutic target for combination of immunotherapy for immune-activated HCC.
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http://dx.doi.org/10.1186/s40425-019-0784-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854886PMC
November 2019
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