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"Ma, Ding"
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Comprehensive metabolomics expands precision medicine for triple-negative breast cancer
Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.
Journal Article
The precision prevention and therapy of HPV‐related cervical cancer: new concepts and clinical implications
Cervical cancer is the third most common cancer in women worldwide, with concepts and knowledge about its prevention and treatment evolving rapidly. Human papillomavirus (HPV) has been identified as a major factor that leads to cervical cancer, although HPV infection alone cannot cause the disease. In fact, HPV‐driven cancer is a small probability event because most infections are transient and could be cleared spontaneously by host immune system. With persistent HPV infection, decades are required for progression to cervical cancer. Therefore, this long time window provides golden opportunity for clinical intervention, and the fundament here is to elucidate the carcinogenic pattern and applicable targets during HPV‐host interaction. In this review, we discuss the key factors that contribute to the persistence of HPV and cervical carcinogenesis, emerging new concepts and technologies for cancer interventions, and more urgently, how these concepts and technologies might lead to clinical precision medicine which could provide prediction, prevention, and early treatment for patients. We discussed the key factors that contribute to HPV persistency and cervical carcinogenesis, the perspective and novel potential technologies for early diagnose and effective prevention of the disease, and more importantly, how this knowledge of basic science may translate into clinic to provide better personalized health care for patients with cervical cancer. This review contributed to the deeper understanding of effective prevention, screening, and treatment of HPV‐related cervical cancer.
Journal Article
Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1–8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%–41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%–75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%–48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of
TOP2A
and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.
Journal Article
A versatile route to fabricate single atom catalysts with high chemoselectivity and regioselectivity in hydrogenation
Preparation of single atom catalysts (SACs) is of broad interest to materials scientists and chemists but remains a formidable challenge. Herein, we develop an efficient approach to synthesize SACs via a precursor-dilution strategy, in which metalloporphyrin (MTPP) with target metals are co-polymerized with diluents (tetraphenylporphyrin, TPP), followed by pyrolysis to N-doped porous carbon supported SACs (M
1
/N-C). Twenty-four different SACs, including noble metals and non-noble metals, are successfully prepared. In addition, the synthesis of a series of catalysts with different surface atom densities, bi-metallic sites, and metal aggregation states are achieved. This approach shows remarkable adjustability and generality, providing sufficient freedom to design catalysts at atomic-scale and explore the unique catalytic properties of SACs. As an example, we show that the prepared Pt
1
/N-C exhibits superior chemoselectivity and regioselectivity in hydrogenation. It only converts terminal alkynes to alkenes while keeping other reducible functional groups such as alkenyl, nitro group, and even internal alkyne intact.
The general synthesis of single atom catalysts (SACs) is of broad interest to chemists but remains a formidable challenge. Here, with the precursor-dilution strategy, the authors successfully prepare 24 different SACs and the Pt SACs exhibit superior chemo- and regio-selectivity in hydrogenation.
Journal Article
Anchoring Cu1 species over nanodiamond-graphene for semi-hydrogenation of acetylene
The design of cheap, non-toxic, and earth-abundant transition metal catalysts for selective hydrogenation of alkynes remains a challenge in both industry and academia. Here, we report a new atomically dispersed copper (Cu) catalyst supported on a defective nanodiamond-graphene (ND@G), which exhibits excellent catalytic performance for the selective conversion of acetylene to ethylene, i.e., with high conversion (95%), high selectivity (98%), and good stability (for more than 60 h). The unique structural feature of the Cu atoms anchored over graphene through Cu-C bonds ensures the effective activation of acetylene and easy desorption of ethylene, which is the key for the outstanding activity and selectivity of the catalyst.
It is highly desired to explore cheap, non-toxic transition metals catalysts for semihydrogenation of acetylene. Here, isolated Cu atoms anchored onto a defective nanodiamond-graphene support exhibit robust catalytic performance in acetylene semihydrogenation in comparison with supported Cu clusters.
Journal Article
Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response
Tumors are not only aggregates of malignant cells but also well-organized complex ecosystems. The immunological components within tumors, termed the tumor immune microenvironment (TIME), have long been shown to be strongly related to tumor development, recurrence and metastasis. However, conventional studies that underestimate the potential value of the spatial architecture of the TIME are unable to completely elucidate its complexity. As innovative high-flux and high-dimensional technologies emerge, researchers can more feasibly and accurately detect and depict the spatial architecture of the TIME. These findings have improved our understanding of the complexity and role of the TIME in tumor biology. In this review, we first epitomized some representative emerging technologies in the study of the spatial architecture of the TIME and categorized the description methods used to characterize these structures. Then, we determined the functions of the spatial architecture of the TIME in tumor biology and the effects of the gradient of extracellular nonspecific chemicals (ENSCs) on the TIME. We also discussed the potential clinical value of our understanding of the spatial architectures of the TIME, as well as current limitations and future prospects in this novel field. This review will bring spatial architectures of the TIME, an emerging dimension of tumor ecosystem research, to the attention of more researchers and promote its application in tumor research and clinical practice.
Journal Article
Ensemble effect for single-atom, small cluster and nanoparticle catalysts
A large family of heterogeneous catalytic reactions require active sites with more than one metal atom, that is, an ensemble of metal atoms. The ensemble requirement, which refers to the minimum number of metal atoms that are needed to catalyse a reaction with optimal efficiency, is a useful metric to evaluate the effectiveness of catalysts for reactions with different site requirements. In this Review, we revisit the traditional ensemble effect and lay out the principles for its incorporation within efficient metal catalysts. Single-atom catalysts can also be described through the ensemble effect theory, as the coordination groups of single-atom catalysts constitute an ensemble that is vital for their reactivity. The understanding of the ensemble requirement for metal catalysts provides insights into catalyst design with both optimized activity and atomic efficiency, and contributes to the development of sustainable heterogeneous catalytic transformations.
Single-atom, small cluster and nanoparticle catalysts feature intriguing reactivity for a variety of transformations, which is often attributed to the properties of specific atomic species. This Review critically revisits the reactivity of such catalysts in term of the ensemble effects that arise from the interaction of multiple metal atoms or single atomic species with neighbouring atoms from supports, additives or surface ligands.
Journal Article
Inverse ZrO2/Cu as a highly efficient methanol synthesis catalyst from CO2 hydrogenation
Enhancing the intrinsic activity and space time yield of Cu based heterogeneous methanol synthesis catalysts through CO
2
hydrogenation is one of the major topics in CO
2
conversion into value-added liquid fuels and chemicals. Here we report inverse ZrO
2
/Cu catalysts with a tunable Zr/Cu ratio have been prepared via an oxalate co-precipitation method, showing excellent performance for CO
2
hydrogenation to methanol. Under optimal condition, the catalyst composed by 10% of ZrO
2
supported over 90% of Cu exhibits the highest mass-specific methanol formation rate of 524 g
MeOH
kg
cat
−1
h
−1
at 220 °C, 3.3 times higher than the activity of traditional Cu/ZrO
2
catalysts (159 g
MeOH
kg
cat
−1
h
−1
). In situ XRD-PDF, XAFS and AP-XPS structural studies reveal that the inverse ZrO
2
/Cu catalysts are composed of islands of partially reduced 1–2 nm amorphous ZrO
2
supported over metallic Cu particles. The ZrO
2
islands are highly active for the CO
2
activation. Meanwhile, an intermediate of formate adsorbed on the Cu at 1350 cm
−1
is discovered by the in situ DRIFTS. This formate intermediate exhibits fast hydrogenation conversion to methoxy. The activation of CO
2
and hydrogenation of all the surface oxygenate intermediates are significantly accelerated over the inverse ZrO
2
/Cu configuration, accounting for the excellent methanol formation activity observed.
Enhancing the intrinsic activity and space time yield of Cu based heterogeneous methanol synthesis catalysts is one of the major topics in CO
2
hydrogenation. Here the authors develop a highly active inverse catalyst composed of fine ZrO
2
islands dispersed on metallic Cu nanoparticles.
Journal Article