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.
.
Mechanoluminescence (ML) is generated during exposures of certain materials to mechanical stimuli. Many solid materials produce ML during their fracturing, however, the irreversibility of ...fracto-induced ML limits the practical applications of these materials. In 1999, Chao-Nan Xu discovered an intense and reproducible ML from trap-controlled materials, including ZnS:Mn2+ and SrAl2O4:Eu2+, and introduced the principles and applications of hybrid inorganic/organic mechanoluminescent (ML) composites, and related sensors to visualize stress/strain in target structures. This discovery has triggered intense research interest in trap-controlled ML materials and composites over the past 2 decades. Notable achievements of this research include the development of trap-controlled materials that exhibit bright ML emission from the ultraviolet to the near infra-red, and multiscale mechano-optical sensitivities. This research has also increased our understanding of the mechanisms of ML phenomena, enabling the rational design of trap-controlled ML materials. Practical applications of ML are also being driven by the discovery that ML composites can serve as “mechano-optical sensitive skin” for structural health diagnosis, stress sensors for biomechanics, and mechanically-activated light sources. This review focuses on the design, synthesis, characterization, optimization and application of trap-controlled ML materials, and concludes with discussions on future directions of ML research and specific challenges to improve ML materials for real-world applications.
Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese ...patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.
Recent realization of high sodium‐ion conductivities (>10−2 S cm−1) in inorganic solid electrolytes (ISEs) at room temperature will certainly trigger a boom in all‐solid‐state sodium batteries ...(ASS‐SBs). However, their electrochemical stable windows and compatibility to high capacity/voltage electrodes are unsatisfactory. Developing ideal ISEs that deliver high Na+ ion conductivities, good electrochemical/chemical stability, and compatible electrode/ISE interface is key for the success of high‐performance ASS‐SBs. In this review, focus is mainly on the fundamentals and strategies to optimize ASS‐SB performances from the aspects of ISE and interface, and note that interfacial issues are also ISE‐related. The latest progress in ISEs, including fundamentals of the sodium‐ion conduction mechanism, key parameters dominating the Na+ ion conduction in terms of crystal structure, lattice dynamics, point defects, and grain boundaries, and prototyping strategies for cell design, are elaborated from the perspectives of material and defect chemistry. The key challenges and future opportunities are discussed, and rational solutions are provided.
This review discusses the fundamentals of sodium ionic conduction in inorganic solid electrolytes (ISEs), identifies the key parameters dominating the sodium ionic conduction, and proposes prototyping strategies for both solid electrolyte and full cell design, from the perspectives of materials and defect chemistry. The key challenges and future opportunities for all‐solid‐state sodium batteries using ISEs are also discussed in detail.
amplification, responsible for 20% of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous ...studies have conferred susceptibility of
mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive.
We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasmas ctDNA samples to detect and quantify genetic alterations.
We identified 2 newly acquired
mutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIs
, and
Interestingly, NIH3T3 cells harboring either mutation exhibited responses to type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKI resistance mechanism.
Our study provides insight into the diversity of mechanisms underlying MET-TKI-induced resistance and highlights the potential of sequential use of MET-TKIs.
.
Transition metal catalyzed C−H phosphorylation remains an unsolved challenge. Reported methods are generally limited in scope and require stoichiometric silver salts as oxidants. Reported here is an ...electrochemically driven RhIII‐catalyzed aryl C−H phosphorylation reaction that proceeds through H2 evolution, obviating the need for stoichiometric metal oxidants. The method is compatible with a variety of aryl C−H and P−H coupling partners and particularly useful for synthesizing triarylphosphine oxides from diarylphosphine oxides, which are often difficult coupling partners for transition metal catalyzed C−H phosphorylation reactions. Experimental results suggest that the mechanism responsible for the C−P bond formation involves an oxidation‐induced reductive elimination process.
Electric cell: Reported herein is an electrochemically driven RhIII‐catalyzed aryl C−H phosphorylation reaction which proceeds through H2 evolution. The method is compatible with a variety of aryl C−H and P−H coupling partners and particularly useful for synthesizing triarylphosphine oxides from diarylphosphine oxides. Experimental results suggest that the mechanism responsible for the C−P bond formation involves an oxidation‐induced reductive elimination process. DG=directing group.
The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as EGFR C797S. In vitro study proved that cells harboring EGFR C797S in trans with T790M are sensitive to ...a combination of first- and third-generation EGFR tyrosine kinase inhibitors. However, this has not been reported clinically.
We performed capture-based sequencing on longitudinal plasma samples obtained at various treatment milestones from a patient with advanced lung adenocarcinoma who was undergoing targeted therapy.
At the development of resistance to osimertinib, the patient’s plasma sample revealed EGFR C797S located in trans with T790M. He achieved partial response accompanied by undetectable C797S after commencement of a combinatorial treatment consisting of erlotinib and osimertinib. After 3 months of progression-free survival, he experienced progressive disease with emergence of EGFR C797S located in cis to T790M.
We report the first clinical evidence of efficacy generated by combination therapy consisting of first- and third-generation EGFR tyrosine kinase inhibitors targeting concomitant EGFR T790M and C797S in trans. We also reveal that the clonal progression of C797S from in trans to in cis at disease progression may serve as a potential resistance mechanism.
Ultrasensitive and sustainable near‐infrared (NIR)‐emitting piezoluminescence is observed from noncentrosymmetric and ferroelectric‐phase Sr3Sn2O7 doped with rare earth Nd3+ ions. Sr3Sn2O7:Nd3+ (SSN) ...with polar A21am structure is demonstrated to emit piezoluminescence of wavelength of 800–1500 nm at microstrain levels, which is enhanced by the ferroelectrically polarized charges in the multipiezo material. These discoveries provide new research opportunities to study luminescence properties of multipiezo and piezo‐photonic materials, and to explore their potential as novel ultrasensitive probes for deep‐imaging of stress distributions in diverse materials and structures including artificial bone and other implanted structures (in vivo, in situ, etc).
Ultrasensitive and sustainable near‐infrared‐emitting piezoluminescence is successfully realized from noncentrosymmetric and ferroelectric‐phase Sr3Sn2O7 doped with rare earth Nd3+ ions. The breakthrough provides new research opportunities to study multipiezo and piezo‐photonic materials, and to explore their potential as novel ultrasensitive probes for deep‐imaging of stress distributions in diverse materials and structures (on‐site, in vivo, etc.).
To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced
mutation-positive non-small-cell lung cancer.
This ...was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non-small-cell lung cancer with
mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m
plus cisplatin 75 mg/m
(neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability.
Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84;
= .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67;
< .001). Observed adverse events reflected those most commonly seen with the two treatments.
The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.
Down‐regulation of microRNA‐26a (miR‐26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the ...roles of miR‐26a in tumor growth and metastasis of HCC and found that miR‐26a was frequently down‐regulated in HCC tissues. Down‐regulation of miR‐26a correlated with HCC recurrence and metastasis. Through gain‐ and loss‐of‐function studies, miR‐26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR‐26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR‐26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin‐6 (IL‐6) was identified as a target of miR‐26a. Knockdown of IL‐6 induced effects on HCC cells similar to those induced by miR‐26a. In contrast, IL‐6 treatment abrogated the effects induced by miR‐26a up‐regulation. Moreover, miR‐26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl‐2, Mcl‐1, cyclin D1, and MMP2. IL‐6 treatment antagonized this effect, while knockdown of IL‐6 by IL‐6 short hairpin RNA (shIL‐6) induced inhibitory effects on the expression of p‐Stat3 and its main target genes, similar to miR‐26a. The messenger RNA and protein levels of IL‐6 inversely correlated with miR‐26a in HCCs. Patients with high miR‐26a or low IL‐6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR‐26a, IL‐6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR‐26a could suppress tumor growth and metastasis of HCC through IL‐6‐Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC. (HEPATOLOGY 2013)
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