The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II-IIIA non-small cell lung cancer (NSCLC). ...However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.
ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus ...vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor (
) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.
From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and
-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat ITT population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.
Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio HR, 0.92; 95% CI, 0.62 to 1.36;
= .674); respective 5-year OS rates were 53.2% and 51.2% (
= .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP (
= .316) and 5y DFS rates were 22. 6% and 23.2% (
= .928), respectively.
Adjuvant therapy with gefitinib in patients with early-stage NSCLC and
mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which ...subtype patients will be responsive to checkpoint blockade are not fully understood.
We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.
We observed that
mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the
comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of
Meanwhile,
or
-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that
or
mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that
or
mutation patients, especially those with co-occurring
mutations, showed remarkable clinical benefit to PD-1 inhibitors.
This work provides evidence that
and
mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy.
.
Cuproptosis, a newly identified form of regulated cell death that is copper‐dependent, offers great opportunities for exploring the use of copper‐based nanomaterials inducing cuproptosis for cancer ...treatment. Here, a glucose oxidase (GOx)‐engineered nonporous copper(I) 1,2,4‐triazolate (Cu(tz)) coordination polymer (CP) nanoplatform, denoted as GOx@Cu(tz), for starvation‐augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be “turned on” for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@Cu(tz)‐mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper‐induced toxicity. The increased intracellular hydrogen peroxide (H2O2) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@Cu(tz). The in vivo experimental results indicate that GOx@Cu(tz) produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis.
An enzyme‐engineered cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in cancer cells is reported, which may invigorate studies pursuing rational design of effective cancer therapy strategies based on cuproptosis.
Flavonoids and isoflavonoids are polyphenolic secondary metabolites usually produced by plants adapting to changing ecological environments over a long period of time. Therefore, their biosynthesis ...pathways are considered as the most distinctive natural product pathway in plants. Seemingly, the flavonoids and isoflavones from fungi and actinomycetes have been relatively overlooked. In this review, we summarized and classified the isoflavones and flavonoids derived from fungi and actinomycetes and described their biological activities. Increasing attention has been paid to bioactive substances derived from microorganism whole-cell biotransformation. Additionally, we described the utilization of isoflavones and flavonoids as substrates by fungi and actinomycetes for biotransformation through hydroxylation, methylation, halogenation, glycosylation, dehydrogenation, cyclisation, and hydrogenation reactions to obtain rare and highly active biofunctional derivatives. Overall, among all microorganisms, actinomycetes are the main producers of flavonoids. In our review, we also summarized the functional genes involved in flavonoid biosynthesis.
Gene silencing holds promise for cancer therapeutics because of its potential to inhibit genes involved in tumor development. However, gene silencing is still restricted by its limited efficacy and ...safety. Nanoscale coordination polymers (CPs) emerge as promising nanocarriers for gene delivery, but their responsiveness and potential therapeutic properties have rarely been explored simultaneously. Here, multifunctional ultrathin 2D nanosheets of Cu(I) 1,2,4‐triazolate CP with a thickness of 4.5 ± 0.8 nm are synthesized using a bottom‐up method. These CP nanosheets can act as both an effective DNAzyme nanocarrier for gene therapy and an intrinsic photosensitizer for hypoxia‐tolerant type I photodynamic therapy (PDT), which is ascribed to the Fenton‐like reaction. Because of the glutathione (GSH)‐responsiveness of the CP nanosheets, DNAzyme‐loaded CP nanosheets exhibit excellent cancer‐cell‐targeting gene silencing of the early growth response factor‐1 (EGR‐1), with messenger RNA inhibited by 84% in MCF‐7 (human breast cancer cells) and only 6% in MCF‐10A (normal human mammary epithelial cells). After tail intravenous injection into MCF‐7‐tumor‐bearing mice, the CP nanosheets loaded with chlorin‐e6‐modified DNAzyme under photoirradiation show a high antitumor efficacy (88.0% tumor regression), demonstrating a promising therapeutic platform with efficient and selective gene silencing and PDT of cancer.
Ultrathin 2D nanosheets of Cu(I) 1,2,4‐triazolate coordination polymer, acting as both stimuli‐responsive nanocarriers of DNAzyme for cancer‐cell‐targeting gene silencing and intrinsic photosensitizers for hypoxia‐tolerant type I photodynamic therapy (PDT), are synthesized by a bottom‐up method. After integrating the DNAzyme with chlorin e6, a type II PDT photosensitizer, the obtained nanoplatform achieves superior therapeutic performance.
Two‐dimensional (2D) materials and ultrathin nanosheets are advantageous for elevating the catalysis performance and elucidating the catalysis mechanism of heterogeneous catalysts, but they are ...mostly restricted to inorganic or organic materials based on covalent bonds. We report an electrochemical/chemical exfoliation strategy for synthesizing metal–organic 2D materials based on coordination bonds. A catechol functionalized ligand is used as the redox active pillar to construct a pillared‐layer framework. When the 3D pillared‐layer MOF serves as an electrocatalyst for water oxidation (pH 13), the pillar ligands can be oxidized in situ and removed. The remaining ultrathin (2 nm) nanosheets of the metal–organic layers are an efficient catalyst with overpotentials as low as 211 mV at 10 mA cm−2 and a turnover frequency as high as 30 s−1 at an overpotential of 300 mV.
MOF slicing: A pillared‐layer metal–organic framework (MOF), in which the catechol functionalized pillars can be oxidized and removed in an electrochemical process, gives ultrathin nanosheets (2 nm). These are efficient electrocatalysts for water oxidation at pH 13 with a low overpotential and high turnover frequency (TOF).
The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 ...patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC.
This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599.
Piwi interacting RNAs (piRNAs) constitute novel small non-coding RNA molecules of approximately 24-31 nucleotides in length that often bind to members of the piwi protein family to play regulatory ...roles. Recently, emerging evidence suggests that in addition to the mammalian germline, piRNAs are also expressed in a tissue-specific manner in a variety of human tissues and modulate key signaling pathways at the transcriptional or post-transcriptional level. In addition, a growing number of studies have shown that piRNA and PIWI proteins, which are abnormally expressed in various cancers, may serve as novel biomarkers and therapeutic targets for tumor diagnostics and treatment. However, the functions of piRNAs in cancer and their underlying mechanisms remain incompletely understood. In this review, we discuss current findings regarding piRNA biogenetic processes, functions, and emerging roles in cancer, providing new insights regarding the potential applications of piRNAs and piwi proteins in cancer diagnosis and clinical treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Developing highly efficient hydrogen evolution reaction (HER) catalysts in alkaline media is considered significant and valuable for water splitting. Herein, it is demonstrated that surface ...reorganization engineering by oxygen plasma engraving on electocatalysts successfully realizes a dramatically enhanced alkaline HER activity. Taking CoP nanowire arrays grown on carbon cloth (denoted as CoP NWs/CC) as an example, the oxygen plasma engraving can trigger moderate CoOx species formation on the surface of the CoP NWs/CC, which is visually verified by the X‐ray absorption fine structure, high‐resolution transmission electron microscopy, and energy‐dispersive spectrometer (EDS) mapping. Benefiting from the moderate CoOx species formed on the surface, which can promote the water dissociation in alkaline HER, the surface reorganization of the CoP NWs/CC realizes almost fourfold enhanced alkaline HER activity and a 180 mV decreased overpotential at 100 mA cm−2, compared with the pristine ones. More interestingly, this surface reorganization strategy by oxygen plasma engraving can also be effective to other electrocatalysts such as free‐standing CoP, Co4N, O‐CoSe2, and C‐CoSe2 nanowires, which verifies the universality of the strategy. This work thus opens up new avenues for designing alkaline HER electrocatalysts based on oxygen plasma engraving.
A generic strategy, oxygen plasma engraving engineering, is used to trigger more efficient hydrogen evolution reaction (HER) catalytic activity on the surface of cobalt phosphide in an alkaline electrolyte. The promotion of HER activity relies on the in situ construction of a CoOx/CoP interface, where the amount of oxide can be precisely controlled to an appropriate value by the plasma engraving time.
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