Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and ...select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
In this work, we developed a sensitive and efficient ratiometric electrochemical method for lipopolysaccharide (LPS) detection using Cu-based metal–organic frameworks (Cu-MOFs) as a catalyst and ...target-triggered quadratic cycles for signal amplification. First, in the presence of target LPS, the conformation change of the specifically designed hairpin probes 1 (HP1) triggered the target cyclic-induced polymerization to produce the output DNA with the aid of phi29 DNA polymerase (phi29). Then, the obtained output DNA hybridized with ferrocene-labeled hairpin probes 2 (Fc-HP2, which were immobilized on the electrode) to generate a nicking endonuclease (N.BstNBI) cleavage site. Thus, with N.BstNBI, the original signal molecules of Fc left from the electrode, and the single-stranded capture-probe-modified sensing interface was obtained. At this time, signal probes conducted by Au-nanoparticles-functionalized Cu-MOFs and labeled hairpin probes 3 (HP3/AuNPs/Cu-MOFs) were hybridized with capture probes for hairpin assembly. Herein, AuNPs/Cu-MOFs were not only used as nanocarriers for immobilizing HP3 but also acted as electroactive materials for signal reporting. With the proposed target-triggered quadratic cycles, the cleavage sites of Fc-HP2 were cut, and capture probes were obtained to hybridize with HP3/AuNPs/Cu-MOFs, which caused the signal decrease of Fc. Then Cu-MOFs were closed to the electrode for the signal increase of Cu-MOFs. Furthermore, when glucose was present in the detection solution, AuNPs/Cu-MOFs catalyzed the oxidation of glucose to realize the enzyme-free signal amplification. By measuring the peak currents ratio of the Cu-MOFs and Fc, the proposed aptasenor for LPS detection showed a low detection limit (0.33 fg/mL) and a wide linear range from 1.0 fg/mL to 100 ng/mL with high accuracy and sensitivity. This ratiometric electrochemical approach is expected to be a valuable strategy for detection of other analytes.
Camrelizumab, an mAb against programmed cell death protein 1 (PD-1), plus nab-paclitaxel exhibited promising antitumor activity in refractory metastatic immunomodulatory triple-negative breast cancer ...(TNBC). Famitinib is a tyrosine kinase inhibitor targeting VEGFR2, PDGFR, and c-kit. We aimed to assess the efficacy and safety of a novel combination of famitinib, camrelizumab, and nab-paclitaxel in advanced immunomodulatory TNBC.
This open-label, single-arm, phase II study enrolled patients with previously untreated, advanced, immunomodulatory TNBC (CD8 IHC staining ≥10%). Eligible patients received 20 mg of oral famitinib on days 1 to 28, 200 mg of i.v. camrelizumab on days 1 and 15, and i.v. nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 in 4-week cycles. The primary endpoint was objective response rate (ORR), as assessed by investigators per RECIST v1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and exploratory biomarkers.
Forty-eight patients were enrolled and treated. Median follow-up was 17.0 months (range, 8.7-24.3). Confirmed ORR was 81.3% 95% confidence interval (CI), 70.2-92.3, with five complete and 34 partial responses. Median PFS was 13.6 months (95% CI, 8.4-18.8), and median DOR was 14.9 months 95% CI, not estimable (NE)-NE. Median OS was not reached. No treatment-related deaths were reported. Among 30 patients with IHC, 13 (43.3%) were programmed death-ligand 1 (PD-L1)-negative, and PD-L1 was associated with favorable response. PKD1 and KAT6A somatic mutations were associated with therapy response.
The triplet regimen was efficacious and well tolerated in previously untreated, advanced, immunomodulatory TNBC. The randomized controlled FUTURE-SUPER trial is under way to validate our findings. See related commentary by Salgado and Loi, p. 2728.
In this work, a sensitive electrochemical aptasensor was designed for lipopolysaccharide (LPS) detection based on Ce-based metal-organic frameworks (Ce-MOFs) and Zn2+ dependent DNAzyme-assisted ...recycling as dual signal amplifiers. Herein, Ce-MOFs were decorated with gold nanoparticles (AuNPs) to obtain AuNPs/Ce-MOFs, and the resultant AuNPs/Ce-MOFs not only acted as nanocarriers to capture -SH terminated hairpin probes 2 (HP2) for acquiring HP2/AuNPs/Ce-MOFs signal probes, but also as catalysts to catalyze the oxidation of ascorbic acid (AA). In the presence of target LPS, report DNA was released from the prepared duplex DNA and then hybridized with hairpin probes 1 (HP1, which were immobilized on the electrode). With the help of Zn2+, report DNA could act as Zn2+ dependent DNAzyme to cleave HP1 circularly. Then a large amount of capture probes were produced on the electrode to combine with HP2/AuNPs/Ce-MOFs signal probes. When the detection solution contained electrochemical substrate of AA, AuNPs/Ce-MOFs could oxide AA to obtain enhanced signal. Under the optimized conditions, this proposed aptasensor for LPS exhibited a low detection limit of 3.3 fg/mL with a wide linear range from 10fg/mL to 100ng/mL.
•AuNPs/Ce-MOFs acted as catalysts to realize enzyme-free signal amplification.•Zn2+dependent DNAzyme were used, which overcame the shortage of protein enzyme.•LPS contents were converted into DNA signal report.
Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC ...samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.
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•The metabolic reprogramming and heterogeneity of TNBC is systematically characterized•TNBCs are classified into three subtypes on the basis of metabolic pathways•Three subtypes show distinct sensitivities to various metabolic inhibitors•Inhibition of LDH enhances tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs
Gong et al. reveal the metabolic heterogeneity of triple-negative breast cancer and identify three metabolic-pathway-based subtypes with distinct molecular features and sensitivities to various metabolic inhibitors. They find that inhibition of lactate dehydrogenase could enhance the anti-PD-1 immunotherapy response in a certain subtype of triple-negative breast cancer.
An enzyme-free electrochemical immunosensor based on the host–guest nanonets of N,N-bis(ferrocenoyl)-diaminoethane/β-cyclodextrins/poly(amidoamine) dendrimer-encapsulated Au nanoparticles ...(Fc-Fc/β-CD/PAMAM-Au) for procalcitonin (PCT) detection has been developed in this study. The signal probe was constructed as follows: amine-terminated β-CD was adsorbed to PAMAM-Au first, and then the prepared Fc-Fc was recognized by the β-CD to form stable host–guest nanonets. Next, secondary antibodies (Ab2) were attached into the formed netlike nanostructure of Fc-Fc/β-CD/PAMAM–Au by chemical absorption between PAMAM-Au and -NH2 of β-CD. Herein, the PAMAM-Au act not only as nanocarriers for anchoring large amounts of the β-CD and Ab2 but also as nanocatalysts to catalyze the oxidation of ascorbic acid (AA) for signal amplification. Moreover, the Fc-Fc could be stably immobilized by the hydrophobic inner cavity of β-CD as well as improving solubility by the hydrophilic exterior of β-CD. With the unique structure of two ferrocene units, Fc-Fc not only affords more electroactive groups to make the electrochemical response more sensitive but also plays a role of combining dispersive β-CD-functionalized PAMAM-Au to form the netlike nanostructure. Furthermore, Fc-Fc exhibits good catalytic activity for AA oxidation. When the detection solution contained AA, the synergetic catalysis of PAMAM-Au and Fc-Fc to AA oxidation could be obtained, realizing enzyme-free signal amplification. The proposed immunosensor provided a linear range from 1.80 pg/mL to 500 ng/mL for PCT detection and a detection limit of 0.36 pg/mL under optimal experimental conditions. Moreover, the immunosensor has shown potential application in clinical detection of PCT.
Cancer is a significant global health concern, and finding effective methods to treat it has been a focus of scientific research. It has been discovered that the growth, invasion, and metastasis of ...tumors are closely related to the environment in which they exist, known as the tumor microenvironment (TME). The immune response interacting with the tumor occurring within the TME constitutes the tumor immune microenvironment, and the immune response can lead to anti-tumor and pro-tumor outcomes and has shown tremendous potential in immunotherapy. A channel called the P2X7 receptor (P2X7R) has been identified within the TME. It is an ion channel present in various immune cells and tumor cells, and its activation can lead to inflammation, immune responses, angiogenesis, immunogenic cell death, and promotion of tumor development. This article provides an overview of the structure, function, and pharmacological characteristics of P2X7R. We described the concept and components of tumor immune microenvironment and the influence immune components has on tumors. We also outlined the impact of P2X7R regulation and how it affects the development of tumors and summarized the effects of drugs targeting P2X7R on tumor progression, both past and current, assisting researchers in treating tumors using P2X7R as a target.
•Comprehensive synthesis of the structure and characteristics of P2X7 receptor.•The pharmacological properties of P2X7 receptor were discussed comprehensively.•The role of P2X7 receptor in tumor immunity was discussed.•It is discussed that P2X7 receptor is a molecular target for tumor therapy.
Damp-heat jaundice syndrome (DHJS) is a diagnostic model of traditional Chinese medicine (TCM) that refers to jaundice caused by damp-heat pathogen invasion. DHJS is the most common clinical ...manifestation of TCM, with yellow skin, yellow eyes and anorexia. ZhiziBaipi Decoction (ZBD) is a classic TCM formula that is effective at treating DHJS and various liver diseases. However, the effective components of ZBD in the context of DHJS and the underlying mechanism are unclear.
This study of ZBD using the DHJS rat model aimed to elucidate the pathobiology of DHJS and the metabolic targets of therapeutic ZBD, construct the network relationship between the components of ZBD and endogenous biomarkers, and clarify the underlying mechanism of ZBD in preventing and treating DHJS.
Using chinmedomics as the core strategy, an animal model was generated, and the therapeutic effect of ZBD was evaluated based on behavioral, histopathological and biochemical indicators. Metabonomics tools were used to identify biomarkers of DHJS, TCM-based serum pharmacochemistry was used to analyze the effective constituents of ZBD, and chinmedomics technology was used to identify ZBD components highly related to DHJS biomarkers.
A total of 42 biomarkers were preliminarily identified, and ZBD significantly affected the levels of 29 of these biomarkers. A total of 59 compounds in ZBD were characterized
. According to chinmedomics analysis, the highly correlated components found in blood were isoformononetin, 3-O-feruloylquinic acid, glycyrrhizic acid, oxyberberine, obaculactone and five metabolites.
Chinmedomics combined with UPLC-MS/MS was used to study the targets and effective constituents of ZBD for the treatment of DHJS.
Wastewater treatment sludge from a primary lead-zinc smelter is characterized as hazardous waste and requires treatment prior to disposal due to its significant arsenic and heavy metals contents. ...This study presents a method for the stabilization of arsenic sludge that uses a slag based curing agent composed of smelting slag, cement clinker and limestone. The Unconfined Compressive Strength (UCS) test, the China Standard Leaching Test (CSLT), and the Toxicity Characteristic Leaching Procedures (TCLP) were used to physically and chemically characterize the solidified sludge. The binder ratio was determined according to the UCS and optimal experiments, and the optimal mass ratio of m (smelting slag): m (cement clinker): m (gypsum sludge): m (limestone) was 70:13:12:5. When the binder was mixed with arsenic sludge using a mass ratio of 1:1 and then maintained at 25 °C for 28 d, the UCS reached 9.30 MPa. The results indicated that the leached arsenic content was always less than 5 mg/L, which is a safe level, and does not contribute to recontamination of the environment. The arsenic sludge from the Zn/Pb metallurgy plant can be blended with cement clinker and smelting slag materials for manufacturing bricks and can be recycled as construction materials.
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•Arsenic sludge was solidified with nonferrous industrial residue.•The utilization ratio of waste is high, and the amount of cement clinker is low.•Solidified samples can be potentially used in the common industrial construction.
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