Publications by authors named "Wenhao Xu"

65 Publications

mA Regulator-Mediated Methylation Modification Model Predicts Prognosis, Tumor Microenvironment Characterizations and Response to Immunotherapies of Clear Cell Renal Cell Carcinoma.

Front Oncol 2021 6;11:709579. Epub 2021 Jul 6.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: This study aims to establish an N6-methyladenosine (mA) RNA methylation regulators-mediated methylation model and explore its role in predicting prognostic accuracy of immune contexture and characterizations of clear cell renal cell carcinoma (ccRCC).

Methods: The mA modification subclasses (mAMS) were identified by unsupervised cluster analysis and three clusters were determined by consensus clustering algorithm in a discovering cohort. Testing and real-world validation cohorts were used to identify predictive responses for immune checkpoint therapies (ICTs) of mAMS.

Results: Prognostic implications landscape of mA regulators in cancers and its differential expression levels in ccRCC patients were identified. Based on discovering cohort, ccRCC were automatically divided into three mAMS, and cluster 3 showed significant worse survival than cluster 1/2. Importantly, it was found that the immune checkpoint molecules expression was significantly elevated in cluster 3. Besides, mA score group (cluster 1&2) have significantly elevated TIDE score compared with mA score group (cluster 3). There was conspicuous tertiary lymphoid tissue, aggressive phenotype, elevated glycolysis, expression of PD-L1, abundance of CD8 T cells, CD4 FOXP3 Treg cells and TCRn immune cells infiltration in the high mA score group. Interestingly, there are significantly increased patients with clinical benefit in mA score group in 368 patients receiving ICTs from testing IMvigor210 (n = 292) and validation FUSCC (n = 55) cohorts.

Conclusion: Our discovery highlights the relationship between tumor epigenetic heterogeneity and immune contexture. Immune-rejection cluster 3 has pro-tumorigenic immune infiltration, and shows significant clinical benefits for ccRCC patients receiving ICTs, enabling patient selection for future clinical treatment.
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http://dx.doi.org/10.3389/fonc.2021.709579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290143PMC
July 2021

Dynamic changes of plasma extracellular vesicle long RNAs during perioperative period of colorectal cancer.

Bioengineered 2021 Dec;12(1):3699-3710

Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.

Extracellular vesicles (EVs) long RNAs (exLRs) have been shown to be indicators for the diagnosis and prognosis of colorectal cancer (CRC); however, the dynamic changes of exLRs during perioperative period and their cellular sources in CRC remains largely unknown. In this study, exLR sequencing (exLR-seq) was performed on plasma samples from three CRC patients at four time points (before surgery [T0], after extubation [T1], 1 day after surgery [T2], and 3 days after surgery [T3]). Bioinformatics approaches were used to investigate the profile and biofunctions of exLRs and their cellular sources. Greater than 12,000 mRNAs and 2,000 lncRNAs were reliably detected in each exLR-seq sample. Compared with T0, there were 110 differentially expressed genes (DEGs) in T1, 60 DEGs in T2, and 50 DEGs in T3. A total of 11 DEGs were found at all three time points and were related to membrane potential. In addition, compared to T0, 22 differentially expressed lncRNAs (DELRs) were found in T1, 19 DELRs in T2, and 38 DELRs in T3. Moreover, only three DELRs were detected at all three time points. Interestingly, EVs from CD8 + T cells, CD4+ memory T cells and NK cells decreased after surgery and the absolute quantity of EVs from immune cells were reduced as well. In summary, this study was the first to characterize the dynamic changes of exLRs during perioperative period and the cellular sources. These findings established the foundation for further studies involving the effects of these dynamically changed exLRs on CRC.
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http://dx.doi.org/10.1080/21655979.2021.1943281DOI Listing
December 2021

Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment.

Int J Biol Sci 2021 1;17(9):2205-2222. Epub 2021 Jun 1.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R. China.

This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of in ccRCC were analyzed and . The large-scale findings suggested a significantly higher expression in ccRCC tissues and the predictive efficacy of for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. In conclusion, the large-scale data first revealed that could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.
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http://dx.doi.org/10.7150/ijbs.58295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241725PMC
June 2021

Preparation of astaxanthin micelles self-assembled by a mechanochemical method from hydroxypropyl β-cyclodextrin and glyceryl monostearate with enhanced antioxidant activity.

Int J Pharm 2021 Jun 12;605:120799. Epub 2021 Jun 12.

National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China; Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, PR China. Electronic address:

This research aimed to overcome the current challenges in the application of natural carotenoid antioxidants, such as their complex preparation processes, low bioavailability and poor drug stability. Herein, a mechanochemical method was used to prepare an inclusion complex (IC) that self-assembles into micelles in aqueous solution and achieves solid-phase loading of astaxanthin (AST). The NMR analysis, thermodynamics study, particle size analysis and electron microscopy image results showed that AST, hydroxypropyl β-cyclodextrin (HPβ-CD) and glyceryl monostearate (GMS) formed self-assembled micelles and maintained good stability in aqueous solution. The antioxidant performance experiments showed that the formation of IC increases free radical scavenging activity. The pharmacokinetic studies showed that the bioavailability of the astaxanthin inclusion complex increased 4-fold. The tissue distribution experiments showed that the astaxanthin inclusion complex targets the liver to exert its antioxidant effects. The proposed method uses an innovative preparation technology to produce an efficient drug delivery system without solvents, and it exerts powerful antioxidant activity against astaxanthin.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120799DOI Listing
June 2021

Single-parameter-tuned synthesis for shape-controlled gold nanocrystals stimulated by iron carbonyl.

J Colloid Interface Sci 2021 May 29;601:773-781. Epub 2021 May 29.

Department of Chemistry, Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, PR China. Electronic address:

Shape-controlled synthesis is essential for functional nanomaterials, allowing deeper insights intothe relationship between the structures and the catalytic properties. Synthesis of nanocrystals with particular morphologies are usually studied independently among various synthetic methods, those underline that different surface capping ligands or shape-directing agents bring about disparate shapes. However, a single quantitative parameter method is still lacking to realize precise control of well-defined morphology nanocrystals, especially anisotropic structures, which is essential to understanding the growth process of nanocrystals. Herein, we proposed a single-parameter-tuned synthesis strategy for preparation of shape-controlled gold nanocrystals by regulating the amount of iron carbonyl, by which we produced highly monodisperse Au nanocrystals with various shapes in organic phase including nanoplates (diameter of 16.02 ± 1.13 nm and thickness of 5.35 ± 0.58 nm), nanorods (length of 37.53 ± 3.73 nm and width of 5.26 ± 0.37 nm) and nanospheres (diameter of 8.26 ± 0.38 nm). The single-parameter-tuned method reveals the dual roles of iron carbonyl for controlling the shapes of gold nanocrystals including reductant and oxidative etchant and empowers versatility in synthetic methodology for other noble metals. Moreover, catalytic activity shifting in shapes of nanocrystals was revealed based on the reduction of 4-nitrophenol, showing that the as-synthesized Au nanoplates displayed the enhanced catalytic performance with the lowest activation energy. Our work provides a brand-new pathway for shape-controlled synthesis of noble-metal nanocrystals and has a strong practical value in application fields.
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http://dx.doi.org/10.1016/j.jcis.2021.05.114DOI Listing
May 2021

Quantized doping of CdS quantum dots with twelve gold atoms.

Chem Commun (Camb) 2021 Jun;57(52):6448-6451

Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Laboratory of Advanced Materials, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Fudan University, Shanghai 200433, China.

Through a bottom-up strategy, CdS quantum dots (QDs) doped with 12 gold atoms in each nanocrystal (NC) were prepared by cation exchange reactions. The (Au12) dopants inside the CdS matrix were directly observed using Cs-corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) images and quantitatively confirmed using the inductively coupled plasma atomic emission spectroscopy (ICP-AES) data. With a photoluminescence quantum yield (PLQY) of 37.5%, the as-prepared (Au12)@CdS QDs emitted light at 635 nm. Due to the injection of excited electrons from the lowest unoccupied molecular orbital (LUMO) of dopants to the conduction band (CB) of CdS, multiple fine peaks were observed in the photoluminescence excitation (PLE) spectra. By using clusters as starting materials, we demonstrate a universal approach for the precise tailoring of dopants and provide a pathway for band energy engineering of doped QDs.
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http://dx.doi.org/10.1039/d1cc02460dDOI Listing
June 2021

Traditional Chinese medicine Bu-Shen-Jian-Pi-Fang attenuates glycolysis and immune escape in clear cell renal cell carcinoma: results based on network pharmacology.

Biosci Rep 2021 Jun;41(6)

Department of Surgery, PuDong branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 1000 Shangnan road, Shanghai 200126, China.

Clear cell renal cell carcinoma (ccRCC) is the most common malignant type of kidney cancer. The present study aims to explore the underlying mechanism and potential targets of the traditional Chinese medicine Bu-Shen-Jian-Pi-Fang (BSJPF) in the treatment of ccRCC based on network pharmacology. After obtaining the complete composition information for BSJPF from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, we analyzed its chemical composition and molecular targets and then established a pharmacological interaction network. Twenty-four significantly differentially expressed genes and nine pathways mainly related to tumor proliferation were identified and screened. Functional enrichment analysis indicated that the potential targets might be significantly involved in glycolysis and the HIF-1 signaling pathway. To further confirm the effect of BSJPF on ccRCC cell proliferation, a BALB/c xenograft mouse model was constructed. Potential targets involved in regulating glycolysis and the tumor immune microenvironment were evaluated using RT-qPCR. VEGF-A expression levels were markedly decreased, and heparin binding-EGF expression was increased in the BSJPF group. BSJPF also inhibited tumor proliferation by enhancing GLUT1- and LDHA-related glycolysis and the expression of the immune checkpoint molecules PD-L1 and CTLA-4, thereby altering the immune-rejection status of the tumor microenvironment. In summary, the present study demonstrated that the mechanism of BSJPF involves multiple targets and signaling pathways related to tumorigenesis and glycolysis metabolism in ccRCC. Our research provides a novel theoretical basis for the treatment of tumors with traditional Chinese medicine and new strategies for immunotherapy in ccRCC patients.
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http://dx.doi.org/10.1042/BSR20204421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202066PMC
June 2021

Inositol hexanicotinate self-micelle solid dispersion is an efficient drug delivery system in the mouse model of non-alcoholic fatty liver disease.

Int J Pharm 2021 Jun 9;602:120576. Epub 2021 Apr 9.

Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China; National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, PR China. Electronic address:

Inositol hexanicotinate (IHN) self-micelle solid dispersion (SD) with glycyrrhizic acid (GA) and arabic gum (AG) was prepared by mechanical ball milling process to improve the solubility, stability of amorphous state, and bioavailability of IHN, which enhanced the treatment of IHN on hyperlipidemia and nonalcoholic fatty liver disease (NAFLD). The physicochemical properties of IHN/GA/AG SDs in solid state were characterized by differential scanning calorimetry, X-ray diffraction studies, and scanning electron microscopy. The characteristics of the sample solutions were analyzed by reverse-phase HPLC, particle characterization, critical micelle concentration, and transmission electron microscopy. Further pharmacokinetic study of this SD formulation in rats showed a significant 3.3-fold increase in bioavailability compared to pure IHN. Moreover, biomarkers in serum and liver of NAFLD mice were significantly ameliorated after oral administration of IHN/GA/AG SDs for 15 days. Altogether, these results establish the mechanochemically prepared IHN/GA/AG SDs as an efficacious formulation for the treatment of hyperlipidemia and NAFLD.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120576DOI Listing
June 2021

Multi-omics reveals novel prognostic implication of SRC protein expression in bladder cancer and its correlation with immunotherapy response.

Ann Med 2021 12;53(1):596-610

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, PR China.

Purpose: This study aims to identify potential prognostic biomarkers of bladder cancer (BCa) based on large-scale multi-omics data and investigate the role of SRC in improving predictive outcomes for BCa patients and those receiving immune checkpoint therapies (ICTs).

Methods: Large-scale multi-comic data were enrolled from the Cancer Proteome Atlas, the Cancer Genome Atlas and gene expression omnibus based on machining-learning methods. Immune infiltration, survival and other statistical analyses were implemented using R software in cancers ( = 12,452). The predictive value of SRC was performed in 81 BCa patients receiving ICT from aa validation cohort ( = 81).

Results: Landscape of novel candidate prognostic protein signatures of BCa patients was identified. Differential BECLIN, EGFR, PKCALPHA, ANNEXIN1, AXL and SRC expression significantly correlated with the outcomes for BCa patients from multiply cohorts ( = 906). Notably, risk score of the integrated prognosis-related proteins (IPRPs) model exhibited high diagnostic accuracy and consistent predictive ability (AUC = 0.714). Besides, we tested the clinical relevance of baseline SRC protein and mRNA expression in two independent confirmatory cohorts ( = 566) and the prognostic value in pan-cancers. Then, we found that elevated SRC expression contributed to immunosuppressive microenvironment mediated by immune checkpoint molecules of BCa and other cancers. Next, we validated SRC expression as a potential biomarker in predicting response to ICT in 81 BCa patient from FUSCC cohort, and found that expression of SRC in the baseline tumour tissues correlated with improved survival benefits, but predicts worse ICT response.

Conclusion: This study first performed the large-scale multi-omics analysis, distinguished the IPRPs ( and ) and revealed novel prediction model, outperforming the currently traditional prognostic indicators for anticipating BCa progression and better clinical strategies. Additionally, this study provided insight into the importance of biomarker SRC for better prognosis, which may inversely improve predictive outcomes for patients receiving ICT and enable patient selection for future clinical treatment.
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http://dx.doi.org/10.1080/07853890.2021.1908588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043611PMC
December 2021

Solubility, Permeability, Anti-Inflammatory Action and In Vivo Pharmacokinetic Properties of Several Mechanochemically Obtained Pharmaceutical Solid Dispersions of Nimesulide.

Molecules 2021 Mar 10;26(6). Epub 2021 Mar 10.

National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.

Nimesulide (NIM, -(4-nitro-2-phenoxyphenyl)methanesulfonamide) is a relatively new nonsteroidal anti-inflammatory analgesic drug. It is practically insoluble in water (<0.02 mg/mL). This very poor aqueous solubility of the drug may lead to low bioavailability. The objective of the present study was to investigate the possibility of improving the solubility and the bioavailability of NIM via complexation with polysaccharide arabinogalactan (AG), disodium salt of glycyrrhizic acid (NaGA), hydroxypropyl-β-cyclodextrin (HP-β-CD) and MgCO. Solid dispersions (SD) have been prepared using a mechanochemical technique. The physical properties of nimesulide SD in solid state were characterized by differential scanning calorimetry and X-ray diffraction studies. The characteristics of the water solutions which form from the obtained solid dispersions were analyzed by reverse phase and gel permeation HPLC. It was shown that solubility increases for all complexes under investigation. These phenomena are obliged by complexation with auxiliary substances, which was shown by H-NMR relaxation methods. The parallel artificial membrane permeability assay (PAMPA) was used for predicting passive intestinal absorption. Results showed that mechanochemically obtained complexes with polysaccharide AG, NaGA, and HP-β-CD enhanced permeation of NIM across an artificial membrane compared to that of the pure NIM. The complexes were examined for anti-inflammatory activity on a model of histamine edema. The substances were administered to CD-1 mice. As a result, it was found that all investigated complexes dose-dependently reduce the degree of inflammation. The best results were obtained for the complexes of NIM with NaGA and HP-β-CD. In noted case the inflammation can be diminished up to 2-fold at equal doses of NIM.
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http://dx.doi.org/10.3390/molecules26061513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998760PMC
March 2021

Research on Preparation of 5-ASA Colon-Specific Hydrogel Delivery System without Crosslinking Agent by Mechanochemical Method.

Pharm Res 2021 Apr 22;38(4):693-706. Epub 2021 Mar 22.

Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, People's Republic of China.

Purpose: This study aims to overcome the challenges of the current oral targeted drug delivery system, such as the complex preparation process, poor biocompatibility, and delayed drug release.

Methods: Here, a non-covalent polymer hydrogel was prepared using the mechanochemical method, and the solid phase loading of 5-amino salicylic acid (5-ASA) was realized.

Results: The results obtained from the thermodynamics study, particle size analysis, and electron microscopy show that chitosan (CS) and sodium alginate (SA) form a pH-sensitive hydrogel under the mechanochemical force and also maintain good stability in aqueous solution. Fluorescent tracers study showed that the pH-sensitive hydrogel could achieve the targeted drug release in the colon and the retention time was over 12 h. Next, in vivo efficacy studies, change in mice body weight, DAI (disease activity index) score, thymus, and spleen index, and the diseased state of the mice colon revealed that the pH-sensitive hydrogel is an improved drug delivery system over 5-ASA API commercial preparations as observed in the efficacy and toxicological studies.

Conclusion: This method uses an innovative preparation technology that without the need of cross-linking agent to produce an efficient colon-targeted drug delivery system for the treatment of ulcerative colitis.
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http://dx.doi.org/10.1007/s11095-021-02993-2DOI Listing
April 2021

Dual Ni/photoredox-catalyzed asymmetric cross-coupling to access chiral benzylic boronic esters.

Nat Commun 2021 Mar 12;12(1):1646. Epub 2021 Mar 12.

Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai, People's Republic of China.

The flourishing Ni/photoredox-catalyzed asymmetric couplings typically rely on redox-neutral reactions. In this work, we report a reductive cross-coupling of aryl iodides and α-chloroboranes under a dual catalytic regime to further enrich the metallaphotoredox chemistry. This approach proceeds under mild conditions (visible light, ambient temperature, no strong base) to access the versatile benzylic boronic esters with good functional group tolerance and excellent enantioselectivities.
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http://dx.doi.org/10.1038/s41467-021-21947-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954797PMC
March 2021

Fatty Acid Synthase Correlates With Prognosis-Related Abdominal Adipose Distribution and Metabolic Disorders of Clear Cell Renal Cell Carcinoma.

Front Mol Biosci 2020 25;7:610229. Epub 2021 Jan 25.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Lipid metabolism reprogramming is a major pathway in tumor evolution. This study investigated fatty acid synthase (FASN) mRNA expression in anthropometric adipose tissue and elucidated the prognostic value and potential mechanism of clear cell renal cell carcinoma (ccRCC). Transcription profiles were obtained from 533 ccRCC samples in The Cancer Genome Atlas (TCGA) cohorts. Real-time quantitative PCR (RT-qPCR) and immunohistochemistry were performed to detect expression in 380 paired ccRCC and normal tissues from the Fudan University Shanghai Cancer Center (FUSCC). Visceral adipose tissue (VAT) and subcutaneous adipose tissue were at the level of the umbilicus as measured by magnetic resonance imaging (MRI). Non-targeted metabolomics and experiments were used to reveal the biological functions of FASN. Increased expression was significantly relevant to advanced T, N, and American Joint Committee on Cancer (AJCC) stages ( < 0.01) and significantly correlated to poor progression-free survival (PFS) and overall survival (OS) of 913 ccRCC patients in FUSCC and TCGA cohorts. Pearson's correlation coefficient indicated that amplification was positively correlated to VAT% ( = 0.772, < 0.001), which significantly correlated to poor PFS (HR = 2.066, = 0.028) and OS (HR = 2.773, = 0.023) in the FUSCC cohort. Transient inhibition or overexpression of significantly regulated A498 and 786O cell proliferation and migration by regulating epithelial-mesenchymal transition. Inhibition of led to a higher apoptotic rate and decreased lipid droplet formation compared with normal control in ccRCC cells. Non-targeted metabolomics showed that decreased lipogenesis might be required to sustain an elevation of glycolytic activity in 786O cells by regulating galactinol, dl-lactate, N-acetylaspartylglutamate, and sucrose, thereby participating in carcinogenesis and progression of ccRCC. This study demonstrated that expression is positively related to aggressive cell proliferation, migration, apoptosis, and lipid droplet formation and regulates metabolic disorders of the ccRCC microenvironment. Additionally, elevated mRNA expression is significantly correlated to the abdominal obesity distribution, especially VAT%, which is a significant predictor of a poor prognosis for ccRCC patients.
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http://dx.doi.org/10.3389/fmolb.2020.610229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868388PMC
January 2021

Extracorporeal Membrane Oxygenation for SARS-CoV-2 Acute Respiratory Distress Syndrome: A Retrospective Study From Hubei, China.

Front Med (Lausanne) 2020 12;7:611460. Epub 2021 Jan 12.

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

The data on long-term outcomes of patients infected by SARS-CoV-2 and treated with extracorporeal membrane oxygenation (ECMO) in China are merely available. A retrospective study included 73 patients infected by SARS-CoV-2 and treated with ECMO in 21 intensive care units in Hubei, China. Data on demographic information, clinical features, laboratory tests, ECMO durations, complications, and living status were collected. The 73 ECMO-treated patients had a median age of 62 (range 33-78) years and 42 (63.6%) were males. Before ECMO initiation, patients had severe respiratory failure on mechanical ventilation with a median PO/FiO of 71.9 [interquartile range (IQR), 58.6-87.0] mmHg and a median PCO of 62 [IQR, 43-84] mmHg on arterial blood analyses. The median duration from symptom onset to invasive mechanical ventilation, and to ECMO initiation was19 [IQR, 15-25] days, and 23 [IQR, 19-31] days. Before and after ECMO initiation, the proportions of patients receiving prone position ventilation were 58.9 and 69.9%, respectively. The median duration of ECMO support was 18.5 [IQR 12-30] days. During the treatments with ECMO, major hemorrhages occurred in 31 (42.5%) patients, and oxygenators were replaced in 21 (28.8%) patients. Since ECMO initiation, the 30-day mortality and 60-day mortality were 63.0 and 80.8%, respectively. In Hubei, China, the ECMO-treated patients infected by SARS-CoV-2 were of a broad age range and with severe hypoxemia. The durations of ECMO support, accompanied with increased complications, were relatively long. The long-term mortality in these patients was considerably high.
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http://dx.doi.org/10.3389/fmed.2020.611460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835137PMC
January 2021

Structural basis for self-cleavage prevention by tag:anti-tag pairing complementarity in type VI Cas13 CRISPR systems.

Mol Cell 2021 03 19;81(5):1100-1115.e5. Epub 2021 Jan 19.

State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address:

Bacteria and archaea apply CRISPR-Cas surveillance complexes to defend against foreign invaders. These invading genetic elements are captured and integrated into the CRISPR array as spacer elements, guiding sequence-specific DNA/RNA targeting and cleavage. Recently, in vivo studies have shown that target RNAs with extended complementarity with repeat sequences flanking the target element (tag:anti-tag pairing) can dramatically reduce RNA cleavage by the type VI-A Cas13a system. Here, we report the cryo-EM structure of Leptotrichia shahii LshCas13a in complex with target RNA harboring tag:anti-tag pairing complementarity, with the observed conformational changes providing a molecular explanation for inactivation of the composite HEPN domain cleavage activity. These structural insights, together with in vitro biochemical and in vivo cell-based assays on key mutants, define the molecular principles underlying Cas13a's capacity to target and discriminate between self and non-self RNA targets. Our studies illuminate approaches to regulate Cas13a's cleavage activity, thereby influencing Cas13a-mediated biotechnological applications.
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http://dx.doi.org/10.1016/j.molcel.2020.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274241PMC
March 2021

An efficient pipeline for ancient DNA mapping and recovery of endogenous ancient DNA from whole-genome sequencing data.

Ecol Evol 2021 Jan 21;11(1):390-401. Epub 2020 Dec 21.

Institute of Vertebrate Paleontology and Paleoanthropology Chinese Academy of Sciences Beijing China.

Ancient DNA research has developed rapidly over the past few decades due to improvements in PCR and next-generation sequencing (NGS) technologies, but challenges still exist. One major challenge in relation to ancient DNA research is to recover genuine endogenous ancient DNA sequences from raw sequencing data. This is often difficult due to degradation of ancient DNA and high levels of contamination, especially homologous contamination that has extremely similar genetic background with that of the real ancient DNA. In this study, we collected whole-genome sequencing (WGS) data from 6 ancient samples to compare different mapping algorithms. To further explore more effective methods to separate endogenous DNA from homologous contaminations, we attempted to recover reads based on ancient DNA specific characteristics of deamination, depurination, and DNA fragmentation with different parameters. We propose a quick and improved pipeline for separating endogenous ancient DNA while simultaneously decreasing homologous contaminations to very low proportions. Our goal in this research was to develop useful recommendations for ancient DNA mapping and for separation of endogenous DNA to facilitate future studies of ancient DNA.
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http://dx.doi.org/10.1002/ece3.7056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790629PMC
January 2021

Tracheostomy in 80 COVID-19 Patients: A Multicenter, Retrospective, Observational Study.

Front Med (Lausanne) 2020 17;7:615845. Epub 2020 Dec 17.

Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.

The outbreak of coronavirus disease 2019 (COVID-19) has led to a large and increasing number of patients requiring prolonged mechanical ventilation and tracheostomy. The indication and optimal timing of tracheostomy in COVID-19 patients are still unclear, and the outcomes about tracheostomy have not been extensively reported. We aimed to describe the clinical characteristics and outcomes of patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who underwent elective tracheostomies. The multi-center, retrospective, observational study investigated all the COVID-19 patients who underwent elective tracheostomies in intensive care units (ICUs) of 23 hospitals in Hubei province, China, from January 8, 2020 to March 25, 2020. Demographic information, clinical characteristics, treatment, details of the tracheostomy procedure, successful weaning after tracheostomy, and living status were collected and analyzed. Data were compared between early tracheostomy patients (tracheostomy performed within 14 days of intubation) and late tracheostomy patients (tracheostomy performed after 14 days). A total of 80 patients were included. The median duration from endotracheal intubation to tracheostomy was 17.5 [IQR 11.3-27.0] days. Most tracheotomies were performed by ICU physician [62 (77.5%)], and using percutaneous techniques [63 (78.8%)] at the ICU bedside [76 (95.0%)]. The most common complication was tracheostoma bleeding [14 (17.5%)], and major bleeding occurred in 4 (5.0%) patients. At 60 days after intubation, 31 (38.8%) patients experienced successful weaning from ventilator, 17 (21.2%) patients discharged from ICU, and 43 (53.8%) patients had died. Higher 60 day mortality [22 (73.3%) vs. 21 (42.0%)] were identified in patients who underwent early tracheostomy. In patients with SARS-CoV-2 pneumonia, tracheostomies were feasible to conduct by ICU physician at bedside with few major complications. Compared with tracheostomies conducted after 14 days of intubation, tracheostomies within 14 days were associated with an increased mortality rate.
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http://dx.doi.org/10.3389/fmed.2020.615845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793766PMC
December 2020

Environmentally-extended input-output and ecological network analysis for Energy-Water-CO metabolic system in China.

Sci Total Environ 2021 Mar 5;758:143931. Epub 2020 Dec 5.

School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China. Electronic address:

Resource and environmental elements as controlling factors for ecologic and socio-economic are crucial to seek new ideas and paths for development and prosperity. In this study, environmentally-extended input-output analysis and ecological network analysis were combined to develop three ecological networks including energy ecological network, water ecological network, and carbon ecological network for searching the complex relationships among different departments for water utilization, energy consumption, and carbon emissions under considering China as a superorganism with various complex metabolic processes and the most fundamental metabolic materials. The embodied ecological elements intensity, the indirect consumption and emissions, the embodied material flows, the ecological relationships, and the dependence intensities among sectors was obtained through transforming the monetary input-output data to physical data from 2007, 2012, and 2017. The results show that the Energy Ecological Network and Water Ecological Network were in a relatively stable state with a mutualism index greater than 1, and the relationship among different sectors in the CO Ecological Network needs to be further adjusted. AM (Advanced Manufacture) and Agr (Agriculture) played the top exporter and importer roles with AM as the largest embodied energy consumer and CO emitter, and Agr as the largest embodied water user. More measures about resource conservation and emission reduction for AM and Agr are desired. Con (construction) had a strong dependence intensity on other sectors with amounts of over 90%. Resources and environmental effects on Con can be improved by increasing the utilization efficiency of intermediate products. The results could provide scientific policy implications and guidelines to promote the stable and healthy operations by revealing the dynamic change of sectors within the Energy-Water-CO metabolic system in China.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143931DOI Listing
March 2021

Network pharmacological systems study of Huang-Lian-Tang in the treatment of glioblastoma multiforme.

Oncol Lett 2021 Jan 6;21(1):18. Epub 2020 Nov 6.

Department of Pathogenic Biology, Medical College, Nantong University, Nantong, Jiangsu 226001, P.R. China.

Glioblastoma multiforme (GBM) has a poor prognosis and its recurrence and mortality rates are high. At present, there is no effective clinical method to control its progression and recurrence. Traditional Chinese Medicine has a high status not only in China, but also in the world. Certain drugs are also used in the clinical treatment of tumor diseases. In clinical practice, Huang-Lian-Tang (HLT) has proven efficacy in treating brain diseases and preventing tumor recurrence. However, the mechanisms of action have remained elusive. The present study explored the potential mechanisms of HLT in the treatment of gliomas based on network pharmacology. First, information on the composition of HLT was obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the composition and targets of the chemical substances contained in the herbs were analyzed. Subsequently, a pharmacological interaction network for HLT was built. Furthermore, the expressed genes of patients with GBM were obtained from Gene Expression Omnibus database and screened. A protein-protein interaction network was then constructed for both sets of data and they were combined with a topology method for analysis. Finally, the screened genes were subjected to enrichment analysis and pathway analysis. A total of 386 candidate targets and 7 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened, which were mainly associated with amino acid metabolism. Gene Ontology enrichment analysis and KEGG signal pathway analysis indicated that these targets are involved in anti-apoptosis, anti-oxidative stress, multicellular biological processes and other physiological and pathological processes related to the occurrence and development of GBM. In conclusion, the present results indicated that the mechanisms of action of HLT against GBM involve multiple targets and signaling pathways that are related to tumorigenesis and progression. The present study not only provided a novel theoretical basis for Traditional Chinese Medicine to treat tumors but also novel ideas for the treatment of GBM.
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http://dx.doi.org/10.3892/ol.2020.12279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681198PMC
January 2021

Dual Nickel- and Photoredox-Catalyzed Reductive Cross-Coupling of Aryl Halides with Dichloromethane via a Radical Process.

Org Lett 2020 Nov 27;22(21):8643-8647. Epub 2020 Oct 27.

Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.

The first catalytic strategy to harness a new chloromethane radical from dichloromethane under dual Ni/photoredox catalytic conditions has been developed. Compared with traditional two-electron reductive process associated with metallic reductants, this method via a single-electron approach can proceed under exceptionally mild conditions (visible light, ambient temperature, no strong base) and exhibits complementary reactivity patterns. It affords a broad scope of many functional groups, including alkenyl, which suffers cyclopropanation in previous routes. The diarylmethane- compounds can be readily available with this transformation.
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http://dx.doi.org/10.1021/acs.orglett.0c03248DOI Listing
November 2020

Phosphosite T674A mutation in kinesin family member 3A fails to reproduce tissue and ciliary defects characteristic of CILK1 loss of function.

Dev Dyn 2021 Feb 7;250(2):263-273. Epub 2020 Oct 7.

Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Background: Kinesin family member 3A (KIF3A) is a molecular motor protein in the heterotrimeric kinesin-2 complex that drives anterograde intraflagellar transport. This process plays a pivotal role in both biogenesis and maintenance of the primary cilium that supports tissue development. Ciliogenesis associated kinase 1 (CILK1) phosphorylates human KIF3A at Thr672. CILK1 loss of function causes ciliopathies that manifest profound and multiplex developmental defects, including hydrocephalus, polydactyly, shortened and hypoplastic bones and alveoli airspace deficiency, leading to perinatal lethality. Prior studies have raised the hypothesis that CILK1 phosphorylation of KIF3A is critical for its regulation of organ development.

Results: We produced a mouse model with phosphorylation site Thr674 in mouse Kif3a mutated to Ala. Kif3a T674A homozygotes are viable and exhibit no skeletal and brain abnormalities, and only mildly reduced airspace in alveoli. Mouse embryonic fibroblasts carrying Kif3a T674A mutation show a normal rate of ciliation and a moderate increase in cilia length.

Conclusion: These results indicate that eliminating Kif3a Thr674 phosphorylation by Cilk1 is insufficient to reproduce the severe developmental defects in ciliopathies caused by Cilk1 loss of function. This suggests KIF3A-Thr672 phosphorylation by CILK1 is not essential for tissue development and other substrates are involved in CILK1 ciliopathies.
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http://dx.doi.org/10.1002/dvdy.252DOI Listing
February 2021

Identification of tumor-infiltrating immune cells and prognostic validation of tumor-infiltrating mast cells in adrenocortical carcinoma: results from bioinformatics and real-world data.

Oncoimmunology 2020 06 23;9(1):1784529. Epub 2020 Jun 23.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Objective: The purpose of this study was to explore the composition of tumor-infiltrating immune cells (TIIC) and prognostic significance of tumor-infiltrating mast cells (TIMC) in adrenocortical carcinoma (ACC).

Methods: The gene expression profiles of ACC were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE90713, GSE12368). The abundance of TIICs in ACC samples was calculated by CIBERSORT algorithm and immunohistochemistry was used to identify mast cells of 39 tumor samples from Fudan University Shanghai Cancer Center (FUSCC). Differentially expressed genes (DEGs) were analyzed by LIMMA package using R software. Survival analysis was analyzed by Kaplan-Meier method and Cox regression models.

Results: The abundance of mast cells ( = .008) was positively correlated with ACC patients' outcome in TCGA cohort and was also positively correlated with both overall survival ( < .05) and progression-free survival ( < .05) in FUSCC cohort. Different TIMC infiltrations showed significant changes in signaling pathways including DNA replication, nuclear chromosome segregation, and meiotic cell cycle process of ACC. In addition, elevated expression of eight hub genes (KIF18A, CDCA8, SKA1, CEP55, BUB1, CDK1, SGOL1, SGOL2) related to the abundance of TIMC in ACC was significantly correlated with the poor prognosis of the patients.

Conclusion: In conclusion, higher TIMC infiltration was positively correlated with ACC patients' outcome in both TCGA and FUSCC cohort. Lower TIMC infiltration and elevated expression of hub genes () are markedly correlated with aggressive progression and poor prognosis, which might shed lights on novel targets for treatment strategies.
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http://dx.doi.org/10.1080/2162402X.2020.1784529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458645PMC
June 2020

Elevated double-strand break repair protein RAD50 predicts poor prognosis in hepatitis B virus-related hepatocellular carcinoma: A study based on Chinese high-risk cohorts.

J Cancer 2020 14;11(20):5941-5952. Epub 2020 Aug 14.

Department of Neurosurgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, 533000, China.

Increasing evidence indicates that RAD50, which is involved in the repair process of DNA double-strand break (DSB), is also involved in cancer outcomes. However, its role in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. This study was designed to investigate the expression of RAD50 and its prognostic value in HBV-related HCC patients. 107 and 100 patients with HBV-related HCC from the Affiliated Hospital of Youjiang Medical University of Nationalities (AHYMUN) and the Affiliated Hospital of Nantong University (AHNU), respectively, were enrolled in the study. The distribution of the categorical clinical-pathological data and the levels of RAD50 expression were compared with a χ test. Immunohistochemistry (IHC) staining of RAD50 was performed. A partial likelihood test based on univariate and multivariate Cox regression analysis was developed to address the influence of independent factors on disease-free survival (DFS) and overall survival (OS). The Oncomine online database was used to analyse and validate the differential expression of RAD50. The Kaplan-Meier method and a log-rank test were performed to assess the influence of RAD50 on survival at different levels. RAD50 was highly expressed in HCC tissues compared to normal tissues and was significantly correlated with OS in the Cancer Genome Atlas (TCGA) cohort. The validation analysis indicated that significantly increased levels of RAD50 were expressed in HCC tissues in the two independent cohorts. In addition, HCC patients with elevated RAD50 expression levels showed poor OS and DFS in the AHYMUN cohort and decreased OS and DFS in the AHNTU cohort. In conclusion, our study reveals that elevated RAD50 expression is significantly correlated with cancer progression and poor survival in HBV-related HCC patients. These data suggest that RAD50 may act as an oncogene and may serve as a promising target for the therapy of HBV-related HCC patients.
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http://dx.doi.org/10.7150/jca.46703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477405PMC
August 2020

An Aqueous Route Synthesis of Transition-Metal-Ions-Doped Quantum Dots by Bimetallic Cluster Building Blocks.

J Am Chem Soc 2020 09 14;142(38):16177-16181. Epub 2020 Sep 14.

Department of Chemistry, Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Collaborative Innovation Center of Chemistry for Energy Materials, Fudan University, Shanghai 200438, China.

Water-soluble doped quantum dots have unique photophysical properties and functionalities as optical labels for bioimaging and chemo-/biosensing. However, doping in quantum dots is not easy due to the dopant-ion size mismatch and "self-purification" effect. Here, we demonstrate a successful preparation of Mn-, Cu-, and Ni-doped CdS quantum dots with bimetallic clusters instead of ions as building blocks under mild aqueous conditions up to gram scale. The representative Mn-doped quantum dots have uniform size, about 3.2 ± 0.5 nm, and emit at 620 nm. The doping concentration can be adjusted in the range 6.4%-25.7%. On the premise of good water solubility, they are stable and nontoxic so as to be directly used for cell imaging. Copper and nickel doping have similar results. Because of the close sizes of bimetallic clusters and the low reaction temperature, the challenges posed by dopant size mismatch and ion diffusion are ignored. X-ray absorption fine structure analysis proves that dopants are inside the quantum dots rather than on the surface, indicating that the "self-purification" effect can be effectively overcome. Furthermore, codoped ZnS quantum dots with adjustable emission are achieved, which validates the versatility of our new approach.
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http://dx.doi.org/10.1021/jacs.0c07274DOI Listing
September 2020

Targeting CPT1B as a potential therapeutic strategy in castration-resistant and enzalutamide-resistant prostate cancer.

Prostate 2020 09 10;80(12):950-961. Epub 2020 Jul 10.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Prostate cancer is characterized by aberrant lipid metabolism, including elevated fatty acid oxidation. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of fatty acid oxidation. This study aimed to determine if CPT1B has a critical role in prostate cancer progression and to identify its regulatory mechanism.

Methods: CPT1B expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases was compared with patient survival data. A tissue microarray was constructed with 60 samples of prostate cancer and immunohistochemically stained for CPT1B. Castration-resistant prostate cancer (CRPC) cell lines 22RV1 and C4-2 in which CPT1B expression had been stably knocked down were established; and cell proliferation, cell cycle distribution, and invasion were investigated by Cell Counting Kit-8 (CCK-8) and colony formation assays, flow cytometry, and Transwell assays, respectively. To examine the impact of androgen receptor (AR) inhibition on CPT1B expression, JASPAR CORE was searched to identify AR-binding sites in CPT1B. Dual luciferase and ChIP assays were performed to confirm CPT1B activity and AR binding, respectively. Differentially expressed genes (DEGs) in prostate cancer underwent gene set enrichment analysis (GSEA). Enzalutamide-resistant C4-2 cells were generated and the mechanism of enzalutamide resistance and downstream signaling pathway changes of CPT1B to C4-2 was explored through CCK-8 test.

Results: CPT1B expression was upregulated in human prostate cancer compared with normal prostate tissue and was associated with poor disease-free survival and overall survival. Silencing of CPT1B resulted in downregulated cell proliferation, reduced S-phase distribution, and lower invasive ability, whereas the opposite was observed in CRPC cells overexpressing CPTB1. DEGS in prostate cancer were correlated with G-protein-coupled receptor signaling, molecular transducer activity, and calcium ion binding. AR may regulate CPT1B expression and activity via specific binding sites, as confirmed by dual luciferase and ChIP assays. The CCK-8 experiment demonstrated that CPT1B overexpression in C4-2 cells did not significantly increase the ability of enzalutamide resistance. However, overexpression of CPT1B in C4-2R cells significantly increased the enzalutamide resistance. Upregulation of CPT1B expression increased AKT expression and phosphorylation.

Conclusions: CPT1B is upregulated in prostate cancer and is correlated with poor prognosis, indicating its potential as a biomarker. AR inhibits the transcription of CPT1B. In the CRPC cell line, overexpression of CPT1B alone cannot promote enzalutamide resistance, but in the drug-resistant line C4-2R, overexpression of CPT1B can promote the resistance of C4-2R to enzalutamide.
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http://dx.doi.org/10.1002/pros.24027DOI Listing
September 2020

GLUT1 is an AR target contributing to tumor growth and glycolysis in castration-resistant and enzalutamide-resistant prostate cancers.

Cancer Lett 2020 08 16;485:45-55. Epub 2020 May 16.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:

Castration-resistant prostate cancer (CRPC) displays a higher F-FDG PET SUV than hormone-sensitive prostate cancer, which suggests a greater need for glucose metabolism in CRPC. Targeting glucose metabolism in cancer cells remains attractive for cancer treatment. Glucose transporters (GLUTs) meditate the first and rate-limiting step of glucose metabolism. Here, we investigated the key mediator of glucose transporters and evaluated its therapeutic value in a preclinical model of CRPC. F-FDG PET showed a higher SUV in CRPC than in hormone-sensitive prostate cancer, and GLUT1 expression positively correlated with SUV and was associated with a worse CRPC outcome. GLUT1 inhibition significantly suppressed cell growth, glycolysis and tumor volume in a xenograft model both in CRPC and enzalutamide-resistant prostate cancer. Chromatin immunoprecipitation and dual luciferase reporter assay showed that androgen receptor (AR) directly bound to the GLUT1 gene promoter to promote GLUT1 transcription. Combining GLUT1 inhibition and enzalutamide remarkably suppressed proliferation and glycolysis and induced apoptosis in CRPC cells. Our results suggest that GLUT1 is an AR target and displays synergistic effects with enzalutamide. GLUT1 may act as a promising therapeutic target in CRPC and enzalutamide-resistant prostate cancer.
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http://dx.doi.org/10.1016/j.canlet.2020.05.007DOI Listing
August 2020

Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex.

Nat Commun 2020 04 29;11(1):2066. Epub 2020 Apr 29.

Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.

Mutations in myosin-VIIa (MYO7A) cause Usher syndrome type 1, characterized by combined deafness and blindness. MYO7A is proposed to function as a motor that tensions the hair cell mechanotransduction (MET) complex, but conclusive evidence is lacking. Here we report that multiple MYO7A isoforms are expressed in the mouse cochlea. In mice with a specific deletion of the canonical isoform (Myo7a-ΔC mouse), MYO7A is severely diminished in inner hair cells (IHCs), while expression in outer hair cells is affected tonotopically. IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A's proposed role in tensioning the tip link. Mature IHCs of Myo7a-ΔC mice degenerate over time, giving rise to progressive hearing loss. Taken together, our study reveals an unexpected isoform diversity of MYO7A expression in the cochlea and highlights MYO7A's essential role in tensioning the hair cell MET complex.
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http://dx.doi.org/10.1038/s41467-020-15936-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190839PMC
April 2020

A hot-blast warming facility for simulating global warming in low-stature crop systems and its application case to assess elevated temperature effects on rice in Central China.

Plant Methods 2020 23;16:57. Epub 2020 Apr 23.

1National Key Laboratory of Crop Genetic Improvement, MOA Key Laboratory of Crop Ecophysiology and Farming System in the Middle Reaches of the Yangtze River, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, 430070 Hubei China.

Background: To study the impact of climate warming on crops, it is crucial to have a warming equipment suitable for their field environment. A facility is needed that can provide suitable combinations of different temperatures at reasonable cost for large plots.

Results: Here, an additional field warming facility option named the hot-blast warming facility (HBWF), which comprised heaters, blowers, wind breaks, and a control board was developed. An application case based on HBWF was carried out to assess elevated temperature effects on rice in Central China during 2015 and 2016. We tested four elevated temperature treatments on four rice cultivars under paddy field conditions and measured yield and its components. Heating convection air directly, the facility could increase the temperature of the rice canopy up to 1-2 °C, which could properly simulate global warming. Considering the costs, the HBWF reduced the operating costs because of its relatively lower power consumption (0.164 kW/m), which was 80% lower than that of Free Air Temperature Increase. Our results demonstrate that the HBWF could build a 25 m homogeneous heating area and had little effect on the relative humidity under a paddy field environment. Warming treatments significantly reduced the grain yield by 4.4-22.7% in 2015, and 30.8-61.9% in 2016, compared to the control. The main contribution to the significant decrease of the grain yields was the decrease in seed setting rate. Moreover, a reduction of 1000-grain weight led to the decline in grain yield. The increasing ranges of the temperature simulated by HBWF were stable in different years, however, whether the elevated treatments demonstrated significant difference on rice growth mainly decided by the basic atmospheric temperature (as the control) during the growth period.

Conclusions: The new warming facility is suitable for field trials to assess elevated temperature combinations and provides an extra equipment option for use in elevated temperature research in the future.
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http://dx.doi.org/10.1186/s13007-020-00598-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181580PMC
April 2020

A Hierarchical Network of Four Regulatory Genes Controlling Production of the Polyene Antibiotic Candicidin in sp. Strain FR-008.

Appl Environ Microbiol 2020 04 17;86(9). Epub 2020 Apr 17.

The State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China

The four regulatory genes to in sp. strain FR-008 form a genetic arrangement that is widely distributed in macrolide-producing bacteria. Our previous work has demonstrated that and are critical for production of the polyene antibiotic candicidin. In this study, we further characterized the roles of the other two regulatory genes, and , focusing on the relationship between these four regulatory genes. Disruption of a single or multiple regulatory genes did not affect bacterial growth, but transcription of genes in the candicidin biosynthetic gene cluster decreased, and candicidin production was abolished, indicating a critical role for each of the four regulatory genes, including and , in candicidin biosynthesis. We found that to , although differentially expressed throughout the growth phase, displayed similar temporal expression patterns, with an abrupt increase in the early exponential phase, coincident with initial detection of antibiotic production in the same phase. Our data suggest that the four regulatory genes to have various degrees of control over structural genes in the biosynthetic cluster under the conditions examined. Extensive transcriptional analysis indicated that complex regulation exists between these four regulatory genes, forming a regulatory network, with and functioning at a lower level. Comprehensive cross-complementation analysis indicates that functional complementation is restricted among the four regulators and unidirectional, with complementing the loss of or - and complementing loss of Our study provides more insights into the roles of, and the regulatory network formed by, these four regulatory genes controlling production of an important pharmaceutical compound. The regulation of antibiotic biosynthesis by species is complex, especially for biosynthetic gene clusters with multiple regulatory genes. The biosynthetic gene cluster for the polyene antibiotic candicidin contains four consecutive regulatory genes, which encode regulatory proteins from different families and which form a subcluster within the larger biosynthetic gene cluster in sp. FR-008. Syntenic arrangements of these regulatory genes are widely distributed in polyene gene clusters, such as the amphotericin and nystatin gene clusters, suggesting a conserved regulatory mechanism controlling production of these clinically important medicines. However, the relationships between these multiple regulatory genes are unknown. In this study, we determined that each of these four regulatory genes is critical for candicidin production. Additionally, using transcriptional analyses, bioassays, high-performance liquid chromatography (HPLC) analysis, and genetic cross-complementation, we showed that FscR1 to FscR4 comprise a hierarchical regulatory network that controls candicidin production and is likely representative of how expression of other polyene biosynthetic gene clusters is controlled.
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http://dx.doi.org/10.1128/AEM.00055-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170484PMC
April 2020

Structural basis of a Tn7-like transposase recruitment and DNA loading to CRISPR-Cas surveillance complex.

Cell Res 2020 02 8;30(2):185-187. Epub 2020 Jan 8.

State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.

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http://dx.doi.org/10.1038/s41422-020-0274-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015053PMC
February 2020
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