Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct ...disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.
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•First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia•Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes•Proteome-informed classification distinguished clinical features within early stages•Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets
Deep proteogenomic landscape of early stage lung adenocarcinoma in a cohort of mostly non-smokers reveals unique drivers and biomarkers, as well as gender-associated mutagenesis.
Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), but T790M ...mutation accounts for most TKI drug resistance. This study used highly sensitive methods to detect T790M before and after TKI therapy and investigated the association of T790M and its mutation frequencies with clinical outcome.
Direct sequencing, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and next-generation sequencing (NGS) were used to assess T790M in the following two cohorts of patients with NSCLC: TKI-naive patients (n = 107) and TKI-treated patients (n = 85). Results were correlated with TKI treatment response and survival.
MALDI-TOF MS was highly sensitive in detecting and quantifying the frequency of EGFR-activating mutations and T790M (detection limits, 0.4% to 2.2%). MALDI-TOF MS identified more T790M than direct sequencing in TKI-naive patients with NSCLC (27 of 107 patients, 25.2% v three of 107 patients, 2.8%, respectively; P < .001) and in TKI-treated patients (before TKI: 23 of 73 patients, 31.5% v two of 73 patients, 2.7%, respectively; P < .001; and after TKI: 10 of 12 patients, 83.3% v four of 12 patients, 33.3%, respectively; P = .0143). The EGFR mutations and their frequencies were confirmed by NGS. T790M was an independent predictor of decreased progression-free survival (PFS) in patients with NSCLC who received TKI treatment (P < .05, multivariate Cox regression).
T790M may not be a rare event before or after TKI therapy in patients with NSCLC with EGFR-activating mutations. The pretreatment T790M mutation was associated with shorter PFS with EGFR TKI therapy in patients with NSCLC.
The optimal initial treatment approach for pneumothorax remains controversial. This systemic review and meta-analysis investigated the effectiveness of small-bore pigtail catheter (PC) drainage ...compared with that of large-bore chest tube (LBCT) drainage as the initial treatment approach for all subtypes of pneumothorax.
PubMed and Embase were systematically searched for observational studies and randomized controlled trials published up to October 9, 2017, that compared PC and LBCT as the initial treatment for pneumothorax. The investigative outcomes included success rates, recurrence rates, complication rates, drainage duration, and hospital stay.
Of the 11 included studies (875 patients), the success rate was similar in the PC (79.84%) and LBCT (82.87%) groups, with a risk ratio of 0.99 (95% CI, 0.93 to 1.05; I2 = 0%). Specifically, PC drainage was associated with a significantly lower complication rate following spontaneous pneumothorax than LBCT drainage (Peto odds ratio: 0.49 95% CI, 0.28 to 0.85; I2 = 29%). In the spontaneous subgroup, PC drainage was associated with a significantly shorter drainage duration (mean difference, −1.51 95% CI, −2.93 to −0.09) and hospital stay (mean difference: −2.54 95% CI, −3.16 to −1.92; P < .001) than the LBCT group.
Collectively, results of the meta-analysis suggest PC drainage may be considered as the initial treatment option for patients with primary or secondary spontaneous pneumothorax. Ideally, randomized controlled trials are needed to compare PC vs LBCT among different subgroups of patients with pneumothorax, which may ultimately improve clinical care and management for these patients.
PROSPERO; No.: CRD42017078481; URL: https://www.crd.york.ac.uk/prospero/.
•Adenocarcinoma can transform into SCLC as a mechanism of resistance to TKIs.•We investigated genetic profiles of combined SCLC/NSCLC patients.•SCLC and NSCLC components showed a high consistency in ...EGFR/TP53/RB1 mutations.•TP53/RB1 inactivation may be an early event in the tumorigenesis of combined SCLC/NSCLC.•The SCLC component may arise from NSCLC via activation of the ASCL1 pathway and PI3K/AKT1 signaling pathway.
Histologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined SCLC/non-small cell lung cancer (NSCLC) have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment.
Four patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel.
The distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases.
Our data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways.
Tuning the Fermi level (
E
F
) in Bi
2
Te
3
topological-insulator (TI) films is demonstrated on controlling the temperature of growth with molecular-beam epitaxy (MBE). Angle-resolved photoemission ...spectra (ARPES) reveal that
E
F
of Bi
2
Te
3
thin films shifts systematically with the growth temperature (
T
g
). The key role that a Bi-on-Te(1) (Bi
Te1
) antisite defect plays in the electronic structure is identified through extended X-ray-absorption fine-structure (EXAFS) spectra at the Bi L
3
-edge. Calculations of electronic structure support the results of fitting the EXAFS, indicating that the variation of
E
F
is due to the formation and suppression of Bi
Te1
that is tunable with the growth temperature. Our findings provide not only insight into the correlation between the defect structure and electronic properties but also a simple route to control the intrinsic topological surface states, which could be useful for applications in TI-based advanced electronic and spintronic devices.
Tuning the Fermi level (
E
F
) in Bi
2
Te
3
topological-insulator (TI) films is demonstrated on controlling the temperature of growth with molecular-beam epitaxy (MBE).
We aimed to evaluate whether different driver mutations have varying impacts on the programmed cell death-ligand 1 (PD-L1) expression of non-small cell lung cancer (NSCLC), and whether the prognostic ...roles of PD-L1 amongst our patients were divergent. This was a single-institute study that included patients with NSCLC. Six driver mutations, PD-L1 status, and the outcomes of treatment were assessed. A total of 1,001 NSCLC patients were included for analysis. Overall, the PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rates were 52.2% and 17.3%, respectively. As compared with wild type lung adenocarcinoma, EGFR-mutant and HER2-mutant patients had similarly low PD-L1 and strong PD-L1 positive rates. BRAF-mutant patients had numerically higher PD-L1 and strong PD-L1 positive rates. Patients with fusion mutation (ALK and ROS1) (aOR 2.32 95% CI 1.10-4.88, P = 0.027 and 2.33 95% CI 1.11-4.89, P = 0.026), KRAS mutation (aOR 2.58 95% CI 1.16-5.75, P = 0.020 and 2.44 95% CI 1.11-5.35, P = 0.026), and non-adenocarcinoma histology (aOR 2.73 95% CI 1.72-4.34, P < 0.001 and 1.93 95% CI 1.13-3.30, P = 0.016) all had significantly higher PD-L1 and strong PD-L1 positive rates. A trend towards longer survival was noted in ROS-1 rearranged and KRAS-mutant patients with strong PD-L1 expression who had received crizotinib and chemotherapy, respectively. In conclusion, individual driver mutations had various impacts on the PD-L1 expression of NSCLC patients. The prognostic role of PD-L1 may also be divergent amongst patients harboring different driver mutations.
In this article, a half-bridge (HB) integrated phase-shifted full-bridge (PSFB) converter with a new center-tapped clamp circuit is proposed to achieve high efficiency in electric vehicle battery ...charging systems. The proposed converter has the benefits of HB integrated PSFB converters, such as the extended zero-voltage-switching range and the reduced conduction loss on the primary side. In addition, by using a new center-tapped clamp circuit, which consists of two diodes and one capacitor, the proposed converter can solve the drawbacks of conventional PSFB converters, such as the substantial circulating current, the severe voltage stress and switching loss in the secondary full-bridge rectifier, and a large output inductor. With these improvements, the efficiency is fairly increased, and the volume of the output inductor is reduced. In order to validate the feasibility of the proposed converter, a 3.3-kW prototype was built and tested.
Objective
In lung cancer patients, most deaths are caused by the distant dissemination of cancer cells. Epithelial–mesenchymal transition (EMT) and collective cell migration are distinct and ...important mechanisms involved in cancer invasion and metastasis. Additionally, microRNA dysregulation contributes significantly to cancer progression. In this study, we aimed to explore the function of miR‐503 in cancer metastasis.
Methods
Molecular manipulations (silencing or overexpression) were performed to investigate the biological functions of miR‐503 including migration and invasion. Reorganization of cytoskeleton was assessed using immunofluorescence and the relationship between miR‐503 and downstream protein tyrosine kinase 7 (PTK7) was assessed using quantitative real‐time PCR, immunoblotting, and reporter assays. The tail vein metastatic animal experiments were performed.
Results
Herein, we demonstrated that the downregulation of miR‐503 confers an invasive phenotype in lung cancer cells and provided in vivo evidence that miR‐503 significantly inhibits metastasis. We found that miR‐503 inversely regulates EMT, identified PTK7 as a novel miR‐503 target, and showed the functional effects of miR‐503 on cell migration and invasion were restored upon reconstitution of PTK7 expression. As PTK7 is a Wnt/planar cell polarity protein crucial for collective cell movement, these results implicated miR‐503 in both EMT and collective migration. However, the expression of PTK7 did not influence EMT induction, suggesting that miR‐503 regulates EMT through mechanisms other than PTK7 inhibition. Furthermore, we discovered that PTK7 mechanistically activates focal adhesion kinase (FAK) and paxillin, thereby controlling the reorganization of the cortical actin cytoskeleton.
Conclusion
Collectively, miR‐503 is capable of governing EMT and PTK7/FAK signaling independently to control the invasion and dissemination of lung cancer cells, indicating that miR‐503 represents a pleiotropic regulator of cancer metastasis and hence a potential therapeutic target for lung cancer.
MiR‐503 is a pleiotropic regulator of lung cancer metastasis, governing both epithelial‐mesenchymal transition (EMT) and EMT‐independent PTK7/FAK signaling.MiR‐503 may represent an attractive target for therapeutic interventions in lung cancer.
JAG1 is a Notch ligand that plays a critical role in multiple signaling pathways. However, the functionality of JAG1 in non-small cell lung cancer (NSCLC) has not been investigated thoroughly. By ...comparison of gene transcripted RNA profiles in the cell line pair with differential invasion ability, we identified JAG1 as a potential metastasis enhancer in lung cancer. Ectopic expression of JAG1 on lung cancer cells enhanced cell migration and invasion as well as metastasis in vitro and in vivo. Conversely, knockdown of JAG1 with siRNA in highly invasive cancer cells led to the reduction of migration and invasion. In clinical analysis, JAG1 mRNA expression was higher in tumors than in adjacent normal tissues in 14 of 20 patients with squamous cell carcinoma (SCC). SCC patients with higher JAG1 transcription had poor overall survival than those with low-transcripted JAG1. Microarray analysis indicated that the enforced JAG1 transcription was associated with an elevated HSPA2 RNA transcription, which played a role in promoting cancer cell migration and invasion. In conclusion, this is the first study that demonstrated that JAG1 might act as a potential prognostic marker and JAG1/HSPA2 axis mediates lung cancer malignancy at least partly.
The impact of different first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)s to the clinical efficacy of osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) ...patients with acquired T790M was still unclear. We enrolled 733 advanced EGFR-mutant NSCLC patients with gefitinib, erlotinib or afatinib as first-line EGFR-TKIs treatment for analysis. 373 patients received re-biopsies after progressive disease to first-line EGFR-TKIs treatment, and the total positive rate of T790M was 51.7%. 151 patients who harbored T790M received osimertinib as subsequent treatment. Among them, the median progression-free survival (PFS) of first-line EGFR-TKI (PFS1) was 14.0 months, and the median PFS of osimertinib (PFS2) was 10.1 months. The median PFS1 + PFS2 was 27.5 months, and the median overall survival from first-line EGFR-TKI was 61.3 months. Concerning different first-line EGFR-TKIs, the median PFS2 was 10.9 months in the gefitinib group, 10.0 months in the erlotinib group, and 6.7 months in the afatinib group (p = 0.534). The median PFS1 + PFS2 was 27.7 months, 26.8 months and 24.0 months in the gefitinib, erlotinib, and afatinib group, respectively (p = 0.575). In conclusion, both first-generation and second-generation EGFR-TKIs sequential osimertinib treatment provided good clinical efficacy in advanced EGFR-mutant NSCLC patients with acquired T790M mutation.
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