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1.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408937

RESUMO

Wilms tumor 1 (WT1) oncoprotein is an intracellular oncogenic transcription factor which is barely expressed in normal adult tissues but over expressed in a variety of leukemias and solid cancers. WT1-derived HLA-A*02:01 T cell epitope, RMFPNAPYL (RMF), is a validated target for T cell-based immunotherapy. We generated two T cell receptor mimic antibody-drug conjugates (TCRm-ADCs), ESK-MMAE, and Q2L-MMAE, against WT1 RMF/HLA-A*02:01 complex with distinct affinities, which mediate specific antitumor activity. Although ESK-MMAE showed higher tumor growth inhibition ratio in vivo, the efficacy of them was not so promising, which might be due to low expression of peptide/HLA targets. Therefore, we explored a bispecific TCRm-ADC that exerted more potent tumor cytotoxicity compared with TCRm-ADCs. Hence, our findings validate the feasibility of the presenting intracellular peptides as the targets of ADCs, which broadens the antigen selection range of antibody-based drugs and provides new strategies for precision medicine in tumor therapy.

2.
Biomed Res Int ; 2019: 8103142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312661

RESUMO

Neoantigens are optimal tumor-specific targets for T-cell based immunotherapy, especially for patients with "undruggable" mutated driver genes. T-cell immunotherapy can be a "universal" treatment for HLA genotype patients sharing same oncogenic mutations. To identify potential neoantigens for therapy in gastric cancer, 32 gastric cancer patients were enrolled in our study. Whole exome sequencing data from these patients was processed by TSNAD software to detect cancer somatic mutations and predict neoantigens. The somatic mutations between different patients suggested a high interpatient heterogeneity. C>A and C>T substitutions are common, suggesting an active nucleotide excision repair. The number of predicted neoantigens was significantly higher in patients at stage T1a compared to in patients at T2 or T4b. Six genes (PIK3CA, FAT4, BRCA2, GNAQ, LRP1B, and PREX2) were found as recurrently mutated driver genes in our study. Combining with highly frequent HLA alleles, several neoantigens derived from six recurrently mutated genes were considered as potential targets for further immunotherapy.

3.
Nanoscale ; 11(27): 13058-13068, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31265041

RESUMO

A natural resource such as peony flower has been employed for the first time as a new carbon precursor to prepare green-emitting carbon nanodots (CDs). The emission peak is situated at 523 nm and the excitation wavelength can be extended to the visible light range (452 nm). Due to the formation of CD-MnO2 nanocomposites, the emission intensity of CDs is sharply reduced as a consequence of Förster resonance energy transfer (FRET). Moreover, glucose can be recognized due to the enzymatic conversion of glucose by glucose oxidase to generate H2O2. The MnO2 nanosheets are reduced to form Mn(ii) ions, and the fluorescence of CDs can be recovered. The fluorescence intensity has been improved linearly based on the increasing concentration of glucose (0.5-250 µM) with a detection limit as low as 0.18 µM. This strategy gives a new selection of eco-friendly precursors in carbon nanomaterials and such a consecutive recognition process provides valuable insights for bio-analysis.

4.
Sci Rep ; 9(1): 8205, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160636

RESUMO

RNA secondary structure may influence many cellular processes, including RNA processing, stability, localization, and translation. Single-nucleotide variations (SNVs) that alter RNA secondary structure, referred to as riboSNitches, are potentially causative of human diseases, especially in untranslated regions (UTRs) and noncoding RNAs (ncRNAs). The functions of somatic mutations that act as riboSNitches in cancer development remain poorly understood. In this study, we developed a computational pipeline called SNIPER (riboSNitch-enriched or depleted elements in cancer genomes), which employs MeanDiff and EucDiff to detect riboSNitches and then identifies riboSNitch-enriched or riboSNitch-depleted non-coding elements across tumors. SNIPER is available at github: https://github.com/suzhixi/SNIPER/ . We found that riboSNitches were more likely to be pathogenic. Moreover, we predicted several UTRs and lncRNAs (long non-coding RNA) that significantly enriched or depleted riboSNitches in cancer genomes, indicative of potential cancer driver or essential noncoding elements. Our study highlights the possibly neglected importance of RNA secondary structure in cancer genomes and provides a new strategy to identify new cancer-associated genes.

5.
Cells ; 8(6)2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216761

RESUMO

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors.

6.
Biosci Rep ; 39(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31085718

RESUMO

The specific functions and clinical significance of miR-940 in endometrial carcinoma (EC) have not been studied. First, we assessed the expression of miR-940 and MRVI1 in EC tissues collected from The Cancer Genome Atlas (TCGA) database and EC cell lines. miR-940 was significantly overexpressed in EC tissues and cell lines, particularly in RL95-2 cells. Correlation analysis showed that miR-940 expression level was remarkably associated with age, grade, and death. Moreover, the overall survival (OS) rate in the miR-940 low expression group was higher, compared with miR-940 high expression group. Univariate and multivariate models demonstrated that miR-940 expression, stage, and age were predictive indicators of OS. Moreover, there was no significance of the proliferation ability among the three EC cell lines (RL95-2, ISK, and KLE). To reveal the biological roles of miR-940, we respectively transfected RL95-2 cells with miR-940 mimics, miR-940 inhibitors, and control to further investigate the cell proliferation ability, and migration as well as invasion potential of RL95-2 cells. The transfection of miR-940 mimics significantly increased the proliferation and migration/invasion ability of RL95-2 cells. MRVI1 was predicted to be a potential target of miR-940 by means of in silico analysis followed by validation using luciferase reporter assays. MRVI1 was correlated with good prognosis. Moreover, forced expression of MRVI1 in miR-940 mimic transfected cells abolished the facilitation of miR-940 on cell proliferation, migration, and invasion of RL95-2 and KLE cells. In conclusion, our study demonstrates that miR-940 might function as a reliable diagnostic and prognostic signature in EC.

8.
Eur J Pharm Sci ; 134: 81-92, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30986472

RESUMO

Antibody fragments, as the products of engineered antibodies, exhibit great potential for cancer therapy and imaging. Antibody fragment drug conjugates (AFDCs), which conjugate the highly specific, low-immunity and small-sized antibody fragments with cytotoxic payloads, can overcome the limitations of traditional IgG format drugs in cancer therapy. In this study, a commercialized anti-CD20 monoclonal antibody, ofatumumab (OFA), was applied to generate two site-specific monomethyl auristain E (MMAE)-conjugated AFDCs (Fab-vcMMAE, Fab-CH3mut-vcMMAE) by Sortase A mediated transpeptidation. Compared with OFA-vcMMAE, the two AFDCs maintained most of the binding affinity and the ability of internalization. In vitro studies revealed that Fab-vcMMAE and OFA-vcMMAE had almost identical IC50 values against CD20-positive cell lines, while Fab-CH3-vcMMAE had a lower anti-tumor activity. In vivo studies showed that Fab-vcMMAE had a significantly higher maximum tolerated dose (MTDs), a 30-fold shorter half-life, and slightly lower antitumor activity within the MTDs than OFA-vcMMAE. The distribution study showed that both of the Fab and Fab-CH3mut had higher penetration rates into the tumors than OFA in a xenograft model. Additionally, no obvious difference in tumor drug accumulation was found between the Fab and OFA groups after the penetration process, but the Fab-CH3mut group exhibited less tumor drug accumulation, possibly contributing to the inferior anti-tumor activity of Fab-CH3mut-vcMMAE in vivo. Overall, we preliminarily demonstrated the characteristics of AFDCs by studying OFA-based AFDCs. Our results revealed that Fab is a promising carrier of MMAE to enhance the anti-tumor activity and increase the safety profile compared with OFA.

9.
J Agric Food Chem ; 67(14): 3871-3878, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30912937

RESUMO

Considerable interest in using lanthanide complexes in optics have been well-known persisted for a long time. But such molecular-based edifices have been excluded from practical application because of their poor thermal or photo stabilities. Here a novel europium embedded layered double hydroxide (Mg-Al LDH-Eu) has been established and such an inorganic-organic framework demonstrates improved thermal performance due to hydrolysis and poly condensation of the trimethoxysilyl-unit. In addition, the incorporation of a functional building block such as ethylenediamine triacetic acid can significantly minimize the negative effects of hydroxyl groups. In the presence of tetracycline (Tc), the nanoprobe exhibits an "off-on" change in aqueous solution, and the red luminescence can be excited in the visible light range (405 nm). It provides a very sensitive signal response to Tc with an excellent linear relation in the range of 0.1 µM to 5.0 µM, and the detection limit of this probe is measured to be 7.6 nM. This nanoplatform exhibits low cytotoxicity during in vitro experiments and can be employed for the detection of tetracycline in 293T cells.


Assuntos
Antibacterianos/análise , Európio/química , Hidróxidos/química , Nanoestruturas/química , Espectrometria de Fluorescência/métodos , Tetraciclina/análise , Animais , Bovinos , Contaminação de Alimentos/análise , Luminescência , Medições Luminescentes/instrumentação , Medições Luminescentes/métodos , Leite/química , Espectrometria de Fluorescência/instrumentação
10.
Mater Sci Eng C Mater Biol Appl ; 99: 1092-1098, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889641

RESUMO

The employment of aggregation induced emission (AIE) species for detecting analytes has become ubiquitous in many applications ranging from environmental monitoring to novel chemical sensing processes. Herein, a new organic building block (4,4',4″,4″'-(ethene-1,1,2,2-trayltetrakis (benzene-4,1-diyl))tetrakis(1-methylpyridin-1-ium) boric acid (TPE-B)) has been synthesized and such chromophore exhibits very weak emission in aqueous solution. The molecule-surfactant interaction can lead to distinguished yellow emissions and the incorporation of sodium dodecyl sulfonate (SDS) will generate morphological changes from irregular organic clusters to aggregated nanoparticles with the size of 45 nm. A six-fold intensity enhancement has been observed and the electrostatic forces are believed to act as the primary role for the selective response to SDS. Based on the in situ established TPE-B-SDS framework, a switched-off effect has been observed in the presence of ClO- and this signal change will allow us to accurately determine the concentration of such reactive oxygen species (ClO-). The limits of detection for SDS and ClO- are calculated to be 54.2 nM and 14.2 nM, respectively. These excellent optical properties have been extended into practical range and the results for the detection of SDS and ClO- in tap water samples are satisfactory. It is anticipated that the responsive probe will provide deeper insights into multi-targets sensing in extensive systems.


Assuntos
Técnicas Biossensoriais/métodos , Nanopartículas/química , Ácidos Bóricos/química , Corantes Fluorescentes/química , Limite de Detecção , Nanopartículas/ultraestrutura , Dodecilsulfato de Sódio/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Eletricidade Estática
11.
Artigo em Inglês | MEDLINE | ID: mdl-30616167

RESUMO

Bacillus anthracis spore causes anthrax to seriously threaten human health and even cause death. 2,6-Pyridinedicarboxylic acid (DPA) is a unique biomarker because it is a major component of Bacillus anthracis spore. Herein, we design europium functionalized silicon quantum dots as a ratiometric fluorescent nanoprobe to detect DPA with high sensitivity and selectivity. With the addition of DPA, the red emission peaks were observed at 618 nm. The novel probe enables ratiometric and sensitive DPA detection over nanomolar concentrations (as low as 1.02 µM). This work provided an efficient background-free and self-calibrating method for the recognition of DPA.


Assuntos
Bacillus anthracis/metabolismo , Biomarcadores/análise , Európio/química , Nanoestruturas/química , Pontos Quânticos/química , Silício/química , Fluorescência , Concentração de Íons de Hidrogênio , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Piridinas/química , Padrões de Referência , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
12.
Genes (Basel) ; 9(10)2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30360443

RESUMO

Diverse distributions of pharmacogenetically relevant variants of highly polymorphic CYP2C9, CYP2D6 and CYPOR genes are responsible for some varied drug responses observed across human populations. There is limited data available regarding the pharmacogenetic polymorphisms and frequency distributions of major allele variants in the Pakistani population. The present in silico mutagenesis study conducted on genotype pharmacogenetic variants and comparative analysis with a global population aims to extend the currently limited pharmacogenetic available evidence for the indigenous Pakistani population. Extracted genomic DNA from 244 healthy individuals' venous blood samples were amplified for distinct variant loci in the CYP2C9, CYP2D6 and CYPOR genes. Two-way sequencing results were compared with standard PubMed data and sequence variant loci confirmed by Chromas. This study revealed significant variations in CYP2C9 (rs1799853, rs1057910 and rs72558189), CYP2D6 (rs16947 and rs1135840), and CYPOR (rs1057868, rs781919285 and rs562750402) variants in intraethnic and interethnic frequency distributions. In silico mutagenesis and three-dimensional protein structural alignment analysis approaches clearly exposed the possible varied impact of rare CYPOR (rs781919285 and rs562750402) single nucleotide polymorphisms (SNPs) and confirmed that the influences of CYP2C9 and CYP2D6 variants are consistent with what was found in earlier studies. This investigation highlighted the need to study pharmacogenetic relevance loci and documentation since evidence could be utilized to elucidate genetic backgrounds of drug metabolism, and provide a basis for future pharmacogenomic studies and adequate dose adjustments in Pakistani and global populations.

13.
Nature ; 562(7728): 605-609, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30333625

RESUMO

Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.

15.
Genomics Proteomics Bioinformatics ; 16(4): 276-282, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30223042

RESUMO

Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database (TSNAdb v1.0), based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen (HLA) allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA). We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients, which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy. TSNAdb is freely available at http://biopharm.zju.edu.cn/tsnadb.

16.
Org Lett ; 20(18): 5840-5844, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30192560

RESUMO

A new and efficient catalytic strategy that combines asymmetric organocatalysis and iodine catalysis was first developed for the one-pot Michael/iodization/SN2 nucleophilic substitution sequential catalytic synthesis of spirodihydrobenzofuran pyrazolones and spirodihydrobenzofuran oxindoles. The approach results in products with moderate to high yields (up to 93%), high to excellent enantioselectivities (up to 99% ee), and excellent diastereoselectivities (up to >99:1 dr). The reaction features simple operation and is metal-free and base-free.

17.
Photochem Photobiol Sci ; 17(10): 1329-1336, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30112558

RESUMO

Carbonaceous materials have long been developed to utilize "nano-spaces" and numerous guest species could be encapsulated. A remarkable fluorescence difference has been observed after newly designed pyropheophorbide-a-appended carbon nanohorns were incorporated in a cellular medium and confocal microscopy was employed for the determination of the intracellular localization. Our study supported the role of carbon nanohorns as carriers of photodynamic therapy (PDT) agents and their heating behavior was discussed. We have developed a theranostic platform based on photosensitizer-conjugated carbon nanostructures and this system has been applied in an animal model. In addition, a negligible toxicity of CNH-Pyro was found in body weight experiments and histopathological examination of the major organs.

18.
Inorg Chem ; 57(15): 8866-8873, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-29984986

RESUMO

A novel optical nanoprobe based on silicon quantum dots (SiQDs) has been assembled through a one-pot low-temperature (40 °C) treatment by using 3-(aminopropyl)trimethoxysilane (APTMS) and ascorbic acid (AA) as two precursors. The water-soluble SiQDs demonstrate intense green luminescence in aqueous environment and the excitation-dependent feature has been explored. Meanwhile, the incorporation of salicylaldehyde (SA) serves to suppress the emission of SiQDs effectively via nucleophilic reaction and an "on-off" change is observed. Furthermore, the addition of Zn2+ can lead to evolution of emission peaks, and the green band at 500 nm gradually shifts toward the blue side at 455 nm. The corresponding ratiometric signal changes ( I455/ I500) can accurately determine the Zn2+ concentration and the limit of detection is calculated to be 0.17 µM in the linear range between 1 and 100 µM. In this research, a molecular logic gate (AND) system has been well established by using SA and Zn2+ as two inputs. The fluorescence emission changes based on SiQDs will shed new light on the development of functional sensors at the nanoscale level.

19.
Spectrochim Acta A Mol Biomol Spectrosc ; 204: 196-202, 2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-29935390

RESUMO

Due to the importance of hypochlorous acid (HClO) in biological and industrial, development of fluorescent probes for HClO has been an active research area. Here, a new red-emitting ratiometric fluorescent probe (P) was synthesized and well defined characterization via NMR, HR-MS, and fluorescence spectrum, which serves as a selective and sensitive probe for ClO- group. The probe showed a ratiometric fluorescent response to hypochlorite at the emission intensities ratio (I480/I612) increasing from 0.28 to 27.46. The emission intensities ratio (I480/I612) was linearly enhanced (I480/I612 = 0.064 X + 0.096) with the ClO- concentration range from 1 to 30 µM. The detection limitation for ClO- in aqueous solution is 0.47 µM. Moreover, this biocompatible red-emitting ratiometric fluorescent probe was utilized to the fluorescence imaging of ClO- in living cells and Zebrafish.

20.
Biomaterials ; 178: 158-169, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29933102

RESUMO

Most tumor-associated proteins are located inside tumor cells and thus are not accessible to current marketed therapeutic monoclonal antibodies or their cytotoxic conjugates. Human leukocyte antigen (HLA) class I can present peptides derived from intracellular tumor-associated proteins and somatically mutated proteins on the cell's surface, forming an HLA/peptide complex as tumor-specific antigens for T cell receptor (TCR) recognition. Therefore, HLA-mediated presentation of intracellular tumor antigen peptides provides a viable way to distinguish tumor cells from normal cells, which is important for broadening antigen selection, especially for antibody-drug conjugates (ADCs) regarding their highly cytotoxic payload. We applied sortase A-mediated conjugation to develop TCR-like ADCs (i.e., EA1 HL-vcMMAE) targeting intracellular MART-1 protein, a melanocyte-differentiating antigen specific for metastatic melanomas, via the cell surface HLA-A2/MART-126-35 peptide complex. Homogenous EA1 HL-vcMMAE (drug to antibody ratio of 4) efficiently eliminated melanoma cells in xenograft mouse models with no obvious toxicity at the therapeutic dosage. Trametinib, an MEK inhibitor serving as an HLA expression enhancing agent, augmented the TL-ADCs' efficacy both in vitro and in vivo by upregulating MART-126-35 peptide presentation, thus providing a strategy for overcoming the limitation of antigen presentation level for TL-ADCs. Hence, our findings validate the strategy of using sortase A-generated TL-ADCs to target tumor-specific intracellular proteins, with or without agents present, to increase presenting TCR epitope peptides.

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