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1.
Cell ; 175(2): 442-457.e23, 2018 10 04.
Article in English | MEDLINE | ID: mdl-30290143

ABSTRACT

Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.


Subject(s)
Antibody-Dependent Cell Cytotoxicity/immunology , Cytophagocytosis/immunology , Macrophages/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antibody-Dependent Cell Cytotoxicity/physiology , B7-H1 Antigen/genetics , B7-H1 Antigen/physiology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Cell Line, Tumor , Cytophagocytosis/physiology , DNA-Binding Proteins/physiology , Disease Models, Animal , Female , Humans , Immunotherapy , Killer Cells, Natural/physiology , Lymphoma/immunology , Macrophages/physiology , Mice , Mice, Inbred NOD , Mice, SCID , Phagocytosis/immunology , Phagocytosis/physiology , Phagosomes/physiology , Receptors, IgG/immunology
2.
Cell ; 173(1): 248-259.e15, 2018 03 22.
Article in English | MEDLINE | ID: mdl-29526463

ABSTRACT

The dynamics of the chromatin regulatory landscape during human early embryogenesis remains unknown. Using DNase I hypersensitive site (DHS) sequencing, we report that the chromatin accessibility landscape is gradually established during human early embryogenesis. Interestingly, the DHSs with OCT4 binding motifs are enriched at the timing of zygotic genome activation (ZGA) in humans, but not in mice. Consistently, OCT4 contributes to ZGA in humans, but not in mice. We further find that lower CpG promoters usually establish DHSs at later stages. Similarly, younger genes tend to establish promoter DHSs and are expressed at later embryonic stages, while older genes exhibit these features at earlier stages. Moreover, our data show that human active transposons SVA and HERV-K harbor DHSs and are highly expressed in early embryos, but not in differentiated tissues. In summary, our data provide an evolutionary developmental view for understanding the regulation of gene and transposon expression.


Subject(s)
Chromatin/metabolism , Embryo, Mammalian/metabolism , Evolution, Molecular , Animals , Binding Sites , CpG Islands , DNA Methylation , DNA Transposable Elements/genetics , Deoxyribonuclease I/metabolism , Down-Regulation , Embryonic Development , Humans , Mice , Octamer Transcription Factor-3/antagonists & inhibitors , Octamer Transcription Factor-3/genetics , Octamer Transcription Factor-3/metabolism , Promoter Regions, Genetic , RNA Interference , RNA, Small Interfering/metabolism , Zygote/metabolism
3.
Cell ; 172(4): 841-856.e16, 2018 02 08.
Article in English | MEDLINE | ID: mdl-29395328

ABSTRACT

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.


Subject(s)
Cell Transformation, Neoplastic/immunology , Drug Resistance, Neoplasm/immunology , Fibroblasts/immunology , Neoplasms/immunology , Neoplastic Stem Cells/immunology , Neprilysin/immunology , Receptors, Chemokine/immunology , Tumor Microenvironment/immunology , A549 Cells , Cell Transformation, Neoplastic/pathology , Fibroblasts/pathology , Humans , MCF-7 Cells , Neoplasm Proteins/immunology , Neoplasms/pathology , Neoplastic Stem Cells/pathology , Receptor, Anaphylatoxin C5a
4.
Cell ; 170(2): 367-381.e20, 2017 Jul 13.
Article in English | MEDLINE | ID: mdl-28709003

ABSTRACT

High-order chromatin structure plays important roles in gene expression regulation. Knowledge of the dynamics of 3D chromatin structures during mammalian embryo development remains limited. We report the 3D chromatin architecture of mouse gametes and early embryos using an optimized Hi-C method with low-cell samples. We find that mature oocytes at the metaphase II stage do not have topologically associated domains (TADs). In sperm, extra-long-range interactions (>4 Mb) and interchromosomal interactions occur frequently. The high-order structures of both the paternal and maternal genomes in zygotes and two-cell embryos are obscure but are gradually re-established through development. The establishment of the TAD structure requires DNA replication but not zygotic genome activation. Furthermore, unmethylated CpGs are enriched in A compartment, and methylation levels are decreased to a greater extent in A compartment than in B compartment in embryos. In summary, the global reprogramming of chromatin architecture occurs during early mammalian development.


Subject(s)
Chromatin/metabolism , Embryo, Mammalian/metabolism , Embryonic Development , Animals , Chromatin/chemistry , CpG Islands , DNA Methylation , DNA Replication , Embryo, Mammalian/chemistry , Epigenesis, Genetic , Female , Germ Cells/metabolism , Male , Metaphase , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Oocytes/cytology , Spermatozoa/metabolism , Zygote/metabolism
5.
Nat Immunol ; 19(10): 1112-1125, 2018 10.
Article in English | MEDLINE | ID: mdl-30224822

ABSTRACT

Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (TH1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell-receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and TH1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.


Subject(s)
Carcinoma/immunology , RNA, Long Noncoding/immunology , T-Lymphocytes, Cytotoxic/immunology , Th1 Cells/immunology , Tumor Escape/genetics , Animals , Apoptosis/immunology , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Carcinoma/genetics , Carcinoma/pathology , Female , Heterografts , Humans , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Mice, Inbred NOD , Mice, SCID , RNA, Long Noncoding/genetics
6.
Nature ; 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39236747

ABSTRACT

Two-terminal monolithic perovskite-silicon tandem solar cells demonstrate huge advantages in power conversion efficiency (PCE) compared to their respective single-junction counterparts1,2. However, suppressing interfacial recombination at the wide-bandgap perovskite/electron transport layer interface, without compromising its superior charge transport performance, remains a significant challenge for perovskite-silicon tandem cells3,4. By exploiting the nanoscale discretely distributed LiF ultrathin layer followed by an additional deposition of diammonium diiodide molecule, we have devised a bilayer intertwined passivation strategy that combines efficient electron extraction with further suppression of nonradiative recombination. We constructed perovskite-silicon tandem devices on double-side textured Czochralski (CZ)-based silicon heterojunction cell, which featured a mildly-textured front surface and a heavily-textured rear surface, leading to simultaneously enhanced photocurrent and uncompromised rear passivation. The resulting perovskite-silicon tandem achieved an independently certified stabilized PCE of 33.89%, accompanied by an impressive fill factor (FF) of 83.0% and an open-circuit voltage (Voc) of nearly 1.97 volts. To our knowledge, this represents the first reported certified efficiency of a two-junction tandem solar cell exceeding the single-junction Shockley-Queisser limit of 33.7%.

7.
Cell ; 157(4): 979-991, 2014 May 08.
Article in English | MEDLINE | ID: mdl-24813617

ABSTRACT

The reprogramming of parental methylomes is essential for embryonic development. In mammals, paternal 5-methylcytosines (5mCs) have been proposed to be actively converted to oxidized bases. These paternal oxidized bases and maternal 5mCs are believed to be passively diluted by cell divisions. By generating single-base resolution, allele-specific DNA methylomes from mouse gametes, early embryos, and primordial germ cell (PGC), as well as single-base-resolution maps of oxidized cytosine bases for early embryos, we report the existence of 5hmC and 5fC in both maternal and paternal genomes and find that 5mC or its oxidized derivatives, at the majority of demethylated CpGs, are converted to unmodified cytosines independent of passive dilution from gametes to four-cell embryos. Therefore, we conclude that paternal methylome and at least a significant proportion of maternal methylome go through active demethylation during embryonic development. Additionally, all the known imprinting control regions (ICRs) were classified into germ-line or somatic ICRs.


Subject(s)
DNA Methylation , Embryonic Development , Gene Expression Regulation, Developmental , Genomic Imprinting , 5-Methylcytosine/metabolism , Animals , CpG Islands , Cytosine/analogs & derivatives , Cytosine/metabolism , Embryo, Mammalian/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Promoter Regions, Genetic
8.
Cell ; 153(4): 773-84, 2013 May 09.
Article in English | MEDLINE | ID: mdl-23663777

ABSTRACT

5-methylcytosine is a major epigenetic modification that is sometimes called "the fifth nucleotide." However, our knowledge of how offspring inherit the DNA methylome from parents is limited. We generated nine single-base resolution DNA methylomes, including zebrafish gametes and early embryos. The oocyte methylome is significantly hypomethylated compared to sperm. Strikingly, the paternal DNA methylation pattern is maintained throughout early embryogenesis. The maternal DNA methylation pattern is maintained until the 16-cell stage. Then, the oocyte methylome is gradually discarded through cell division and is progressively reprogrammed to a pattern similar to that of the sperm methylome. The passive demethylation rate and the de novo methylation rate are similar in the maternal DNA. By the midblastula stage, the embryo's methylome is virtually identical to the sperm methylome. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos.


Subject(s)
DNA Methylation , Embryo, Nonmammalian/metabolism , Oocytes/metabolism , Spermatozoa/metabolism , Zebrafish/embryology , Zebrafish/genetics , 5-Methylcytosine/analysis , Animals , Epigenesis, Genetic , Female , Germ Cells/metabolism , Male , Zebrafish/metabolism
9.
Brief Bioinform ; 25(2)2024 Jan 22.
Article in English | MEDLINE | ID: mdl-38385873

ABSTRACT

Lysine lactylation (Kla) is a newly discovered posttranslational modification that is involved in important life activities, such as glycolysis-related cell function, macrophage polarization and nervous system regulation, and has received widespread attention due to the Warburg effect in tumor cells. In this work, we first design a natural language processing method to automatically extract the 3D structural features of Kla sites, avoiding potential biases caused by manually designed structural features. Then, we establish two Kla prediction frameworks, Attention-based feature fusion Kla model (ABFF-Kla) and EBFF-Kla, to integrate the sequence features and the structure features based on the attention layer and embedding layer, respectively. The results indicate that ABFF-Kla and Embedding-based feature fusion Kla model (EBFF-Kla), which fuse features from protein sequences and spatial structures, have better predictive performance than that of models that use only sequence features. Our work provides an approach for the automatic extraction of protein structural features, as well as a flexible framework for Kla prediction. The source code and the training data of the ABFF-Kla and the EBFF-Kla are publicly deposited at: https://github.com/ispotato/Lactylation_model.


Subject(s)
Lysine , Natural Language Processing , Amino Acid Sequence , Protein Domains , Protein Processing, Post-Translational
10.
Nature ; 583(7814): 133-138, 2020 07.
Article in English | MEDLINE | ID: mdl-32528174

ABSTRACT

Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms1-3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models4-6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a 'trap' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-ß-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.


Subject(s)
Breast Neoplasms/pathology , DNA/metabolism , Extracellular Traps/genetics , Membrane Proteins/metabolism , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Neutrophils/metabolism , Actinin/metabolism , Animals , Cell Line, Tumor , Cell Movement , Female , Humans , Liver/pathology , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Membrane Proteins/genetics , Mice , Prognosis , Protein Serine-Threonine Kinases/metabolism , Signal Transduction
11.
Acc Chem Res ; 57(6): 870-883, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38424009

ABSTRACT

ConspectusTo cope with the increasingly global greenhouse effect and energy shortage, it is urgent to develop a feasible means to convert anthropogenic excess carbon dioxide (CO2) into energy resources. The photocatalytic CO2 reduction reaction (CO2RR) coupled with the water oxidation reaction (WOR), known as artificial photosynthesis, is a green, clean, and promoting strategy to deal with the above issues. Among the reported photocatalytic systems for CO2 reduction, the main challenge is to achieve WOR simultaneously due to the limited charge separation efficiency and complicated dynamic process. To address the problem, scientists have assembled two nanosemiconductor motifs for CO2RR and WOR into a heterojunction photocatalyst to realize artificial photosynthesis. However, it is difficult to clearly explore the corresponding catalytic mechanism and establish an accurate structure-activity relationship at the molecular level for their aperiodic distribution and complicated structural information. Standing on the shoulders of the heterojunction photocatalysts, a new-generation material, hetero-motif molecular junction (HMMJ) photocatalysts, has been developed and studied by our laboratory. A hetero-motif molecular junction is a class of crystalline materials with a well-defined and periodic structure, adjustable assembly mode, and semiconductor-like properties, which is composed of two predesigned motifs with oxidation and reduction, respectively, by coordination or covalent bonds. The intrinsic properties make these catalysts susceptible to functional modifications to improve light absorption and electrical conductivity. The small size and short distance of the motifs can greatly promote the efficiency of photogenerated electron-hole separation and migration. Based on these advantages, they can be used as potential excellent photocatalysts for artificial photosynthesis. Notably, the explicit structural information determined by single-crystal or powder X-ray diffraction can provide a visual platform to explore the reaction mechanism. More importantly, the connection number, spatial distance, interaction, and arrangement mode of the structural motifs can be well-designed to explore the detailed structure-activity relationship that can be hardly studied in nanoheterojunction photocatalyst systems. In this regard, HMMJ photocatalysts can be a new frontier in artificial photosynthesis and serve as an important bridge between molecular photocatalysts and solid photocatalysts. Thus, it is very important to summarize the state-of-the-art of the HMMJ photocatalysts used for artificial photosynthesis and to give in-depth insight to promote future development.In this Account, we have summarized the recent advances in artificial photosynthesis using HMMJ photocatalysts, mainly focusing on the results in our lab. We present an overview of current knowledge about developed photocatalytic systems for artificial photosynthesis, introduce the design schemes of the HMMJ photocatalysts and their unique advantages as compared to other photocatalysts, summarize the construction strategies of HMMJ photocatalysts and their application in artificial photosynthesis, and explain why hetero-motif molecular junctions can be promising photocatalysts and show that they provide a powerful platform for studying photocatalysis. The structure-activity relationship and charge separation dynamics are illustrated. Finally, we bring our outlook on present challenges and future development of HMMJ photocatalysts and their potential application prospects on other photocatalytic reaction systems. We believe that this Account will afford important insights for the construction of high-efficiency photocatalysts and guidance for the development of more photocatalytic systems in an atom-economic, environmentally friendly, and sustainable way.

12.
Nature ; 576(7786): 306-310, 2019 12.
Article in English | MEDLINE | ID: mdl-31801998

ABSTRACT

In the interphase of the cell cycle, chromatin is arranged in a hierarchical structure within the nucleus1,2, which has an important role in regulating gene expression3-6. However, the dynamics of 3D chromatin structure during human embryogenesis remains unknown. Here we report that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is re-established during embryogenesis. Notably, blocking zygotic genome activation (ZGA) can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before ZGA, and is then highly expressed at the ZGA stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during ZGA in human embryos requires CTCF expression. Our results indicate that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis.


Subject(s)
CCCTC-Binding Factor/metabolism , Chromatin , CCCTC-Binding Factor/genetics , Embryo, Mammalian , Embryonic Development , Gene Expression Regulation , Humans , Male , Spermatozoa/metabolism
13.
Proc Natl Acad Sci U S A ; 119(40): e2210550119, 2022 10 04.
Article in English | MEDLINE | ID: mdl-36161955

ABSTRACT

Constructing redox semiconductor heterojunction photocatalysts is the most effective and important means to complete the artificial photosynthetic overall reaction (i.e., coupling CO2 photoreduction and water photo-oxidation reactions). However, multiphase hybridization essence and inhomogeneous junction distribution in these catalysts extremely limit the diverse design and regulation of the modes of photogenerated charge separation and transfer pathways, which are crucial factors to improve photocatalytic performance. Here, we develop molecular oxidation-reduction (OR) junctions assembled with oxidative cluster (PMo12, for water oxidation) and reductive cluster (Ni5, for CO2 reduction) in a direct (d-OR), alternant (a-OR), or symmetric (s-OR) manner, respectively, for artificial photosynthesis. Significantly, the transfer direction and path of photogenerated charges between traditional junctions are obviously reformed and enriched in these well-defined crystalline catalysts with monophase periodic distribution and thus improve the separation efficiency of the electrons and holes. In particular, the charge migration in s-OR shows a periodically and continuously opposite mode. It can inhibit the photogenerated charge recombination more effectively and enhance the photocatalytic performance largely when compared with the traditional heterojunction models. Structural analysis and density functional theory calculations disclose that, through adjusting the spatial arrangement of oxidation and reduction clusters, the energy level and population of the orbitals of these OR junctions can be regulated synchronously to further optimize photocatalytic performance. The establishment of molecular OR junctions is a pioneering important discovery for extremely improving the utilization efficiency of photogenerated charges in the artificial photosynthesis overall reaction.


Subject(s)
Carbon Dioxide , Light , Photosynthesis , Oxidation-Reduction , Water/chemistry
14.
Proteomics ; 24(1-2): e2300185, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37847886

ABSTRACT

Lactylation, as a novel posttranslational modification, is essential for studying the functions and regulation of proteins in physiological and pathological processes, as well as for gaining in-depth knowledge on the occurrence and development of many diseases, including tumors. However, few studies have examined the protein lactylation of one whole organism. Thus, we studied the lactylation of global proteins in Caenorhabditis elegans to obtain an in vivo lactylome. Using an MS-based platform, we identified 1836 Class I (localization probabilities > 0.75) lactylated sites in 487 proteins. Bioinformatics analysis showed that lactylated proteins were mainly located in the cytoplasm and involved in the tricarboxylic acid cycle (TCA cycle) and other metabolic pathways. Then, we evaluated the conservation of lactylation in different organisms. In total, 41 C. elegans proteins were lactylated and homologous to lactylated proteins in humans and rats. Moreover, lactylation on H4K80 was conserved in three species. An additional 238 lactylated proteins were identified in C. elegans for the first time. This study establishes the first lactylome database in C. elegans and provides a basis for studying the role of lactylation.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Humans , Animals , Rats , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , Citric Acid Cycle , Metabolic Networks and Pathways , Proteome/metabolism
15.
J Am Chem Soc ; 146(30): 20649-20659, 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39018421

ABSTRACT

When catalytic reactions are interfered with by radiation sources, thorium clusters are promising as potential catalysts due to their superior radiation resistance. However, there is currently very little research on the design synthesis and catalytic application of radiation-stable thorium clusters. In this work, we have elaborately engineered and fabricated three high-nuclear thorium cluster catalysts denoted as Th12L3-MA12, Th12L3-MA6-BF6, and Th12L3-Fcc12, which did not undergo any significant alterations in their molecular structures and compositions after irradiation with 690 kGy γ-rays. We systematically investigated the photocatalytic/thermocatalytic properties of these radiation-resistant thorium clusters for the first time and found that γ-rays could not alter their catalytic activities. In addition, it was found that ligand engineering could modulate the catalytic activity of thorium clusters, thus expanding the range of catalytic applications of thorium clusters, including reduction reactions (nitroarene reduction) and some oxidation reactions (N-heterocyclic oxidative dehydrogenation and diphenylmethane oxidation). Meanwhile, all of these organic transformation reactions achieved a >80% conversion and nearly 100% product selectivity. Radiation experiments combined with DFT calculations showed that the synergistic catalysis of thorium-oxo core and ligands led to the generation of specific active species (H+, O2•-, or tBuO/tBuOO•) and activation of substrate molecules, thus achieving superior catalytic performance. This work is not only the first to develop radiation-resistant thorium cluster catalysts to perform efficient redox reactions but also provides design ideas for the construction of high-nuclearity thorium clusters under mild conditions.

16.
J Am Chem Soc ; 146(32): 22797-22806, 2024 Aug 14.
Article in English | MEDLINE | ID: mdl-39087792

ABSTRACT

The construction of isotypic high-nuclearity inorganic cages with identical pristine parent structure and increasing nuclearity is highly important for molecular growth and structure-property relationship study, yet it still remains a great challenge. Here, we provide an in situ growth approach for successfully synthesizing a series of new giant hollow polymolybdate dodecahedral cages, Mo250, Mo260-I, and Mo260-E, whose structures are growth based on giant polymolybdate cage Mo240. Remarkably, they show two pathways of nuclear growth based on Mo240, that is, the growth of 10 and 20 Mo centers on the inner and outer surfaces to afford Mo250 and Mo260-I, respectively, and the growth of 10 Mo centers both on the inner and outer surfaces to give Mo260-E. To the best of our knowledge, this is the first study to display the internal and external nuclear growth of a giant hollow polyoxometalate cage. More importantly, regular variations in structure and nuclearity confer these polymolybdate cages with different optical properties, oxidative activities, and hydrogen atom transfer effect, thus allowing them to exhibit moderate to excellent photocatalytic performance in oxidative cross-coupling reactions between different unactivated alkanes and N-heteroarenes. In particular, Mo240 and Mo260-E with better comprehensive abilities can offer the desired coupling product with yield up to 92% within 1 h.

17.
Cancer Sci ; 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39101880

ABSTRACT

This study investigated the role of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. Our findings highlighted the critical role of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. In conclusion, our study elucidates the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas, providing insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.

18.
Mol Med ; 30(1): 130, 2024 Aug 24.
Article in English | MEDLINE | ID: mdl-39182021

ABSTRACT

BACKGROUND: Vascular calcification is a common vascular lesion associated with high morbidity and mortality from cardiovascular events. Antibiotics can disrupt the gut microbiota (GM) and have been shown to exacerbate or attenuate several human diseases. However, whether antibiotic-induced GM disruption affects vascular calcification remains unclear. METHODS: Antibiotic cocktail (ABX) treatment was utilized to test the potential effects of antibiotics on vascular calcification. The effects of antibiotics on GM and serum short-chain fatty acids (SCFAs) in vascular calcification mice were analyzed using 16 S rRNA gene sequencing and targeted metabolomics, respectively. Further, the effects of acetate, propionate and butyrate on vascular calcification were evaluated. Finally, the potential mechanism by which acetate inhibits osteogenic transformation of VSMCs was explored by proteomics. RESULTS: ABX and vancomycin exacerbated vascular calcification. 16 S rRNA gene sequencing and targeted metabolomics analyses showed that ABX and vancomycin treatments resulted in decreased abundance of Bacteroidetes in the fecal microbiota of the mice and decreased serum levels of SCFAs. In addition, supplementation with acetate was found to reduce calcium salt deposition in the aorta of mice and inhibit osteogenic transformation in VSMCs. Finally, using proteomics, we found that the inhibition of osteogenic transformation of VSMCs by acetate may be related to glutathione metabolism and ubiquitin-mediated proteolysis. After adding the glutathione inhibitor Buthionine sulfoximine (BSO) and the ubiquitination inhibitor MG132, we found that the inhibitory effect of acetate on VSMC osteogenic differentiation was weakened by the intervention of BSO, but MG132 had no effect. CONCLUSION: ABX exacerbates vascular calcification, possibly by depleting the abundance of Bacteroidetes and SCFAs in the intestine. Supplementation with acetate has the potential to alleviate vascular calcification, which may be an important target for future treatment of vascular calcification.


Subject(s)
Acetates , Anti-Bacterial Agents , Fatty Acids, Volatile , Gastrointestinal Microbiome , Vascular Calcification , Animals , Gastrointestinal Microbiome/drug effects , Vascular Calcification/metabolism , Vascular Calcification/etiology , Vascular Calcification/drug therapy , Mice , Fatty Acids, Volatile/metabolism , Acetates/pharmacology , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacology , Male , Osteogenesis/drug effects , RNA, Ribosomal, 16S/genetics , Disease Models, Animal , Mice, Inbred C57BL , Vancomycin/adverse effects , Vancomycin/pharmacology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/drug effects
19.
Oncologist ; 29(8): 667-671, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-38970465

ABSTRACT

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Receptor, ErbB-2 , Trastuzumab , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Receptor, ErbB-2/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , Trastuzumab/therapeutic use , Trastuzumab/pharmacology , Male , Middle Aged , United States , United States Food and Drug Administration , Drug Approval , Aged , Immunoconjugates/therapeutic use , Immunoconjugates/pharmacology , Immunoconjugates/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Camptothecin/pharmacology , Camptothecin/adverse effects , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology
20.
Small ; : e2405118, 2024 Aug 14.
Article in English | MEDLINE | ID: mdl-39140191

ABSTRACT

The development of polymer binders is necessary to meet the growing demands of modern energy storage technologies. While catechol-containing materials are proven successful in silicon anodes, their application in organic batteries remains unexplored. In this contribution, the synthesis of four polymers are described with nearly identical side chain composition but varying backbone structures. The materials are used to investigate the effect of polymer backbone structure on the binding abilities of catechol-containing materials. Comparative analysis with the commonly used polyvinylidene fluoride (PVDF) binder aims to address two critical questions: 1) Can catechol-rich polymers replace PVDF for use in organic cathodes? and 2) Does the choice of polymer backbone affect the performance of the battery?. The investigation reveals that supramolecular interactions, such as π-π stacking and coordination bonding, are pivotal features of catechol binders. Among the catechol-rich polymers, the polyacrylate binder stands out, likely attributed to its high flexibility. Additionally, introducing an oxygen atom into a catechol-rich polynorbornene enhances lithium-ion conductivity and rate performance. Overall, the findings highlight the viability of catechol-containing polymers as organic cathode binders, and that the choice of polymer backbone is a crucial factor for their use as lithium-ion battery binder materials.

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