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2.
EMBO Mol Med ; : e14296, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34845836

RESUMO

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU-MP-5 as a new-generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU-MP-5. In addition, XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU-MP-5 as a novel selective ALK inhibitor with high potency and selectivity. XMU-MP-5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.

3.
Transl Oncol ; 15(1): 101261, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34768099

RESUMO

Tobacco smoking is the major cause of non-small-cell-lung cancer (NSCLC). However, it is barely known how smoking impact the tumor immune environment (TIME) of lung cancer. We integrated single-cell RNA-seq and bulk RNA-seq data from several studies to systematically study the impact of smoking on T cells in treatment naïve NSCLC patients. We defined a set of smoking-induced differentially expressed genes (SIDEGs) in different cells in TIME.. Specifically, we defined a smoking-related tumor-specific Treg subset, ADAM12+ CTLA4+ Tregs according to the trajectory analysis and highly express genes in cell adhesion pathways and lipid metabolism. Using independent datasets from treatment naïve patients, we found that the fraction of ADAM12+ CTLA4+ Tregs are significantly increased in patients with smoking history. Moreover, the fraction of ADAM12+ CTLA4+ Tregs are positively correlated with the fraction of exhausted T cells. Additionally, we reconstructed the spatial organization of the tumor immune microenvironment and found that ADAM12+ CTLA4+ Tregs more actively communicate with LAYN+CD8+ exhausted T cells compared with ADAM12-CTLA4+ Tregs. Our data demonstrate that smoking induced a unique subset of tumor-specific activated Tregs which interact with exhausted T cells in the TIME. Our findings not only explained how smoking impact the TIME but also provide new targets and biomarkers for precision immunotherapy of lung cancer.

4.
Cell Prolif ; : e13153, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34773310

RESUMO

'Human retinal pigment epithelial cells' is the first set of guidelines on human retinal pigment epithelial cells in China, jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research. This standard specifies technical requirements, test methods, inspection rules, instructions for usage, labelling requirements, packaging requirements, storage requirements and transportation requirements and waste disposal requirements for human retinal pigment epithelial cells, which is applicable to quality control during the process of manufacturing and testing of human retinal pigment epithelial cells. It was originally released by the Chinese Society for Cell Biology on 9 January 2021. We hope that publication of these guidelines will promote institutional establishment, acceptance and execution of proper protocols and accelerate the international standardization of human retinal pigment epithelial cells for applications.

5.
Cell Prolif ; : e13150, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34708452

RESUMO

'Requirements for human cardiomyocytes', jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research, is the first guideline for human cardiomyocytes in China. This standard specifies the technical requirements, test methods, test regulations, instructions for use, labelling requirements, packing requirements, storage requirements, transportation requirements and waste disposal requirements for human cardiomyocytes, which is designed to normalize and standardize human cardiomyocyte research and production. It was originally released by the China Society for Cell Biology on 9 January 2021. We hope that the publication of this guideline will promote institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardization of human cardiomyocytes for applications.

6.
Front Immunol ; 12: 722273, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34526995

RESUMO

Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4+ helper T cells including TFH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4+ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4+ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4+ helper T cells.

7.
Angew Chem Int Ed Engl ; 60(49): 25766-25770, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34585481

RESUMO

Platinum (Pt) is the most effective bench-marked catalyst for producing renewable and clean hydrogen energy by electrochemical water splitting. There is demand for high HER catalytic activity to achieve efficient utilization and minimize the loading of Pt in catalysts. In this work, we significantly boost the HER mass activity of Pt nanoparticles in Ptx /Co to 8.3 times higher than that of commercial Pt/C by using Co/NC heterojunctions as a heterogeneous version of electron donors. The highly coupled interfaces between Co/NC and Pt metal enrich the electron density of Pt nanoparticles to facilitate the adsorption of H+ , the dissociation of Pt-H bonds and H2 release, giving the lowest HER overpotential of 6.9 mV vs. RHE at 10 mA cm-2 in acid among reported HER electrocatalysts. Given the easy scale-up synthesis due to the stabilization of ultrafine Pt nanoparticles by Co/NC solid ligands, Ptx /Co can even be a promising substitute for commercial Pt/C for practical applications.

8.
Membranes (Basel) ; 11(9)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34564490

RESUMO

This work focuses on the energy analysis of the membrane concentration systems that process traditional Chinese medicine extracts with dynamic properties incorporated, particularly for reverse osmosis (RO) and membrane distillation (MD) processes. The evaluation of process energy consumption was achieved by integrating the empirical properties correlations of Brix and other characteristics properties of the feed (e.g., density and heat capacity). The dynamic SEC analysis for RO process was largely dependent on the feed pressure, reported at 50 kWh/m3 at feed pressure of 0.9 MPa with less than 50% water removal. The occurrence of foaming at above 50% water removal caused discrepancies between the simulated flux results and the experimentally acquired results in RO, whereas the estimated dynamic SEC for MD process did not show a strong correlation with the temperatures selected in this study, ranging from 900 to 1000 kWh/m3. This approach can be adapted into the design and zoptimization for the concentration process of other herbal extracts by membrane technologies, allowing comprehensive understanding into the energy analysis in future study.

9.
Adv Sci (Weinh) ; 8(20): e2100009, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34398529

RESUMO

Two-dimensional (2D) van der Waals (vdW) materials have garnered considerable attention for their unique properties and potentials in a wide range of fields, which include nano-electronics/optoelectronics, solar energy, and catalysis. Meanwhile, challenges in the approaches toward achieving high-performance devices still inspire the search for new 2D vdW materials with precious properties. In this study, via molecular beam epitaxy, for the first time, the vdW SnI2 monolayer is successfully fabricated with a new structure. Scanning tunneling microscopy/spectroscopy characterization, as corroborated by the density functional theory calculation, indicates that this SnI2 monolayer exhibits a band gap of ≈2.9 eV in the visible purple range, and an indirect- to direct-band gap transition occurs in the SnI2 bilayer. This study provides a new semiconducting 2D material that is promising as a building block in future electronics/optoelectronics.

10.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34287641

RESUMO

Mucus produced by goblet cells in the gastrointestinal tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been well studied. Here, we identify that Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in defects in goblet cell autophagy and mucus secretion, leading to an impaired gut microenvironment and dysbiosis. Subsequently, due to changes in microbiota and disruption in microbiome metabolites of short-chain fatty acids, Foxo1 deficiency results in altered organization of tight junction proteins and enhanced susceptibility to intestinal inflammation. Our study demonstrates that Foxo1 is crucial for IECs to establish commensalism and maintain intestinal barrier integrity by regulating goblet cell function.


Assuntos
Proteína Forkhead Box O1/metabolismo , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/fisiologia , Muco/metabolismo , Animais , Autofagia/fisiologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/microbiologia , Disbiose/genética , Ácidos Graxos Voláteis/metabolismo , Feminino , Proteína Forkhead Box O1/genética , Células Caliciformes/patologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Mucina-2/metabolismo , Simbiose/fisiologia
11.
Angew Chem Int Ed Engl ; 60(38): 20711-20716, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34313361

RESUMO

NOx - reduction acts a pivotal part in sustaining globally balanced nitrogen cycle and restoring ecological environment, ammonia (NH3 ) is an excellent energy carrier and the most valuable product among all the products of NOx - reduction reaction, the selectivity of which is far from satisfaction due to the intrinsic complexity of multiple-electron NOx - -to-NH3 process. Here, we utilize the Schottky barrier-induced surface electric field, by the construction of high density of electron-deficient Ni nanoparticles inside nitrogen-rich carbons, to facilitate the enrichment and fixation of all NOx - anions on the electrode surface, including NO3 - and NO2 - , and thus ensure the final selectivity to NH3 . Both theoretical and experimental results demonstrate that NOx - anions were continuously captured by the electrode with largely enhanced surface electric field, providing excellent Faradaic efficiency of 99 % from both electrocatalytic NO3 - and NO2 - reduction. Remarkably, the NH3 yield rate could reach the maximum of 25.1 mg h-1 cm-2 in electrocatalytic NO2 - reduction reaction, outperforming the maximum in the literature by a factor of 6.3 in neutral solution. With the universality of our electrocatalyst, all sorts of available electrolytes containing NOx - pollutants, including seawater or wastewater, could be directly used for ammonia production in potential through sustainable electrochemical technology.

12.
Cancer Res ; 81(16): 4205-4217, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34215622

RESUMO

The somatic landscape of the cancer genome results from different mutational processes represented by distinct "mutational signatures." Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor-immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers. SIGNIFICANCE: The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.

14.
J Colloid Interface Sci ; 604: 810-822, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34303174

RESUMO

Harmful bacterial flourish with the increase in environmental pollution and pose a great threat to human health. Thus, developing new and efficient antibacterial materials is imperative to reduce the pollution caused by traditional sterilization materials and improve sterilization efficiency. In this study, a new photocatalytic antibacterial material was developed to achieve an efficient antibacterial effect. Ti3C2Tx@CuS composites were synthesized by simple hydrothermal method, by which copper sulfide (CuS) nanoparticles were anchored on the surface of Ti3C2Tx to sharply improve the photocatalytic its antibacterial ability. Ti3C2Tx@CuS exhibits excellent antibacterial activity against Escherichia coli and Staphylococcus aureus with bactericidal rates of 99.6% and 99.1%, respectively. Photoluminescence spectroscopy (PL), decay time PL, photocurrent test, electrochemical impedance spectroscopy and finite element method showed that the formation of Ti3C2Tx@CuS heterojunction promoted the separation of electrons and holes, improved the electron transport efficiency, and elevated the generation of reactive oxygen species. Moreover, Ti3C2Tx@CuS has a stronger photothermal effect and causes more heat release than CuS to improve antibacterial performance. The Ti3C2Tx@CuS heterojunction has a broad application prospect in the disinfection and antibacterial fields.


Assuntos
Cobre , Nanopartículas , Cobre/farmacologia , Desinfecção , Humanos , Sulfetos/farmacologia , Titânio
15.
BMC Med Genomics ; 14(1): 142, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059054

RESUMO

BACKGROUND: Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses. RESULTS: We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells. CONCLUSIONS: In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis.

16.
Cancer Med ; 10(11): 3700-3714, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33978320

RESUMO

Genome-wide association studies (GWAS) have reported a handful of loci associated with lung cancer risk, of which the pathogenic pathways are largely unknown. We performed cis-expression quantitative trait loci (eQTL) mapping for 376 lung cancer related GWAS loci in 227 TCGA lung adenocarcinoma (LUAD) and reported two risk loci as eQTL of miRNA. Among the miRNAs in association with lung cancer risk, we further predicted and validated miR-3130-5p as an intermediate modulator of risk loci 2q33 and the tumor suppressor NDUFS1. We assessed the phenotypic impacts of the interaction between miR-3130-5p and NDUFS1 in both lung cancer cell lines and mice xenograft models. As a result, miR-3130-5p directly regulates the expression of NDUFS1 and the corresponding tumor invasiveness, migration and epithelial-mesenchymal transition (EMT). Our findings provide important clues for the pathogenic mechanism of 2q33 in lung carcinogenesis which informs clinical diagnosis and prognosis of LUAD. We performed a cis-eQTL analysis for 376 lung cancer risk loci based on the expression profiles of 251 miRNAs in a cohort of 227 TCGA lung adenocarcinoma. We report a novel pathogenic pathway of 2q33 via miR-3130-5p and NDUFS1.

17.
Oncogene ; 40(24): 4151-4166, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34050266

RESUMO

Emerging evidences suggest that long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and cancer progression. Here, the aim of this study is to investigate the biological function of long intervening noncoding RNA Linc00284 in colorectal cancer (CRC). The expression levels of Linc00284, miR-27a and c-Met were evaluated by qPCR and/or Western blotting. Immunohistochemistry was used to detect the expression of Ki67 and Phh3 in tumor tissues. The interaction between Linc00284, miR-27a and c-Met was validated by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell function experiments, including CCK-8, wound-healing and transwell invasion assays, were conducted. The in vivo studies were performed with the subcutaneous tumor xenograft mouse models. Our findings reveal that Linc00284 is upregulated in CRC tissues and colorectal cancer cell lines HCT116 and SW480 in comparison with corresponding para-carcinoma tissues and human fetal colonic mucosa cells FHC. High expression of Linc00284 in tumor tissues is associated with tumor metastasis and predicts a poor clinical outcome in CRC patients. Serum Linc00284 is increased, while miR-27a is decreased in CRC patients compared to healthy controls. ROC curve analysis indicates that serum Linc00284 and miR-27a produce the area under the curve (AUC) value of at 0.8151 and 0.7316 in patients with colorectal cancer compared to healthy individuals, respectively. Additionally, results in vitro and in vivo experiments suggest that Linc00284 silencing significantly suppresses CRC cell proliferation and/or invasion. Mechanistically, Linc00284 promotes c-Met expression by acting as miR-27a sponge, leading to the activation of downstream signaling pathways, thereby causing malignant phenotypes of CRC cells. Taken together, Linc00284 exhibits oncogenic function and the disturbance of Linc00284/miR-27a/c-Met regulatory axis contributes to CRC progression, providing new insight into the pathogenesis of colorectal cancer. Importantly, the expression levels of serum Linc00284 and miR-27a may serve as clinical biomarkers for CRC diagnosis.

18.
Sci Total Environ ; 767: 144181, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33450590

RESUMO

Ultra-low pressure gravity-driven membrane (GDM) systems have the potential to be significantly less costly and complex than conventional membranes for water treatment applications. To build upon this inherent advantage, this study assesses the reuse of recycled membranes in GDM systems for producing drinking water. Two reverse osmosis spiral-wound modules were recycled into nanofiltration (NF)-like and ultrafiltration (UF)-like membranes via controlled exposure to free chlorine. To operate the recycled membranes, two housing devices, based on a simple fitting and an advanced end-caps design, were developed. The recycled membrane systems were tested under a range of conditions (submerged vs. external system configuration and continuous vs. intermittent filtration mode). Synthetic river water feed solutions were used in the tests where performance, fouling, and clogging were measured. NF-like recycled membranes resulted in poor salt rejection and low permeability (~1.7 L m-2 h-1 bar-1), but also in high rejection (>81%) of dissolved organic carbon. UF-like recycled membranes maintained their capacity to reject biopolymers (BP) (>74%) and featured up to 18-fold higher permeate rate than NF-like recycled membranes. The optimized operating conditions were found when the recycled membranes were housed in the end-caps device and operated intermittently (relaxation time plus forward flushing). Flushing reduced the fouling accumulation inside the membrane (only 12% and 40% of BP accumulation was observed in the NF-like and UF-like, respectively). However, the end-caps-based device was estimated to be more expensive during the economic analysis. To address this techno-economic trade-off, a decision-making tree was developed to select the appropriate configuration based upon the implementation context. Overall, this study concludes that these designs can serve as robust, low-cost (water production cost <1 USD ct. yr. L-1), and light-weight GDM alternatives. This study is beneficial for developing compact GDM systems based on recycled spiral-wound membranes for both rural areas and emergency response.

19.
Front Microbiol ; 11: 571847, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329430

RESUMO

Gut microbiota (GM) modifies the intrahepatic immune microenvironment, but the underlying mechanisms remain poorly understood. Liver fibrosis-associated imprinting is predicted to be reflected in GM. This study investigated the link between GM and the intrahepatic T cell receptor (TCR) immune repertoire (IR), and whether GM modulates the intrahepatic immune microenvironment via TCR IR during liver fibrosis. We analyzed the correlation between GM and TCR IR during liver fibrogenesis. Accordingly, 16S rRNA gene sequencing (16S-seq) and bulk immune repertoire sequencing (IR-seq) were performed to characterize GM and intrahepatic TCR IR. Fecal microbial transplant (FMT) and TCRß knockout (TcrbKO) mouse models were employed to determine the biological link between GM and TCR IR in liver fibrosis. We found that GM and intrahepatic TCR IR are highly correlated, with both showing reduced diversity and centralized distribution during liver fibrosis. The restoration of normal intestinal microbiota may reshape intrahepatic TCR IR and delay liver fibrosis. Interestingly, TCR IR ablation abrogated the impact of GM on liver fibrogenesis. Furthermore, GM modulated hepatic stellate cell (HSC) activation via TCR IR-mediated intrahepatic immune milieu. Our study demonstrates that GM, which exhibits cross-talk with the intrahepatic TCR IR, influences the intrahepatic immune microenvironment and liver fibrosis progression.

20.
Cell Prolif ; 53(12): e12926, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33146418

RESUMO

The standard 'General requirements for stem cells' is the first set of general guidelines for stem cell research and production in China, jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research. This standard specifies the classification, ethical requirements, quality requirements, quality control requirements, detection control requirements and waste disposal requirements of stem cells, which is applicable to stem cell research and production. It was firstly released by the Chinese Society for Cell Biology on 1 August 2017 and was further revised on 30 April 2020. We hope that publication of these guidelines will promote institutional establishment, acceptance, and execution of proper protocols, and accelerate the international standardization of stem cells for clinical development and therapeutic applications.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Pluripotentes/citologia , Transplante de Células-Tronco , Células-Tronco/citologia , Linhagem da Célula/fisiologia , Células-Tronco Embrionárias/citologia , Humanos
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