Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

A novel tool to evaluate and quantify radiation pneumonitis: A retrospective analysis of correlation of dosimetric parameters with volume of pneumonia patch.

Introduction: In lung cancer, radiation-induced lung injury (RILI) or radiation pneumonitis (RP) are major concerns after radiotherapy. We investigated the correlation between volumes of RP lesions and their RP grades after radiotherapy. Methods and materials: We retrospectively collected data from patients with non-small lung cancer that received curative doses to the thorax without undergoing chest radiotherapy before this treatment course. The post-treatment computed tomography (CT) image was used to register to the planning CT to evaluate the correlation between dosimetric parameters and volume of pneumonia patch by using deformable image registration. Results: From January 1, 2019, to December 30, 2020, 71 patients with non-small cell lung cancer with 169 sets of CT images met our criteria for evaluation. In all patient groups, we found the RPv max and RP grade max to be significant (p<0.001). Some parameters that were related to the dose-volume histogram (DVH) and RP were lung Vx (x=1-66 Gy, percentage of lung volume received ≥x Gy), and mean lung dose. Comparing these parameters of the DVH with RP grade max showed that the mean lung dose and lung V1-V31 were significantly correlated. The cut-off point for the occurrence of symptoms in all patient groups, the RPv max value, was 4.79%, while the area under the curve was 0.779. In the groups with grades 1 and 2 RP, the dose curve of 26 Gy covered ≥80% of RP lesions in >80% of patients. Patients who had radiotherapy in combination with chemotherapy had significantly shorter locoregional progression-free survival (p=0.049) than patients who received radiation therapy in combination with target therapy. Patients with RPv max >4.79% demonstrated better OS (p=0.082). Conclusion: The percentage of RP lesion volume to total lung volume is a good indicator for quantifying RP. RP lesions can be projected onto the original radiation therapy plan using coverage of the 26 Gy isodose line to determine whether the lesion is RILI.

Auxin plays a role in the adaptation of rice to anaerobic germination and seedling establishment.

Auxin is well known to stimulate coleoptile elongation and rapid seedling growth in the air. However, its role in regulating rice germination and seedling establishment under submergence is largely unknown. Previous studies revealed that excessive levels of indole-3-acetic acid(IAA) frequently cause the inhibition of plant growth and development. In this study, the high-level accumulation of endogenous IAA is observed under dark submergence, stimulating rice coleoptile elongation but limiting the root and primary leaf growth during anaerobic germination (AG). We found that oxygen and light can reduce IAA levels, promote the seedling establishment and enhance rice AG tolerance. miRNA microarray profiling and RNA gel blot analysis results show that the expression of miR167 is negatively regulated by submergence; it subsequently modulates the accumulation of free IAA through the miR167-ARF-GH3 pathway. The OsGH3-8 encodes an IAA-amido synthetase that functions to prevent free IAA accumulation. Reduced miR167 levels or overexpressing OsGH3-8 increase auxin metabolism, reduce endogenous levels of free IAA and enhance rice AG tolerance. Our studies reveal that poor seed germination and seedling growth inhibition resulting from excessive IAA accumulation would cause intolerance to submergence in rice, suggesting that a certain threshold level of auxin is essential for rice AG tolerance.

Id2 exerts tumor suppressor properties in lung cancer through its effects on cancer cell invasion and migration.

Background: Despite advances in prognosis and treatment of lung adenocarcinoma (LADC), a notable non-small cell lung cancer subtype, patient outcomes are still unsatisfactory. New insight on novel therapeutic strategies for LADC may be gained from a more comprehensive understanding of cancer progression mechanisms. Such strategies could reduce the mortality and morbidity of patients with LADC. In our previous study, we performed cDNA microarray screening and found an inverse relationship between inhibitor of DNA binding 2 (Id2) expression levels and the invasiveness of LADC cells. Materials and Methods: To identify the functional roles of Id2 and its action mechanisms in LADC progression, we successfully established several Id2-overexpressing and Id2-silenced LADC cell clones. Subsequently, we examined in vitro the effects exerted by Id2 on cell morphology, proliferation, colony formation, invasive, and migratory activities and examined in vivo those exerted by Id2 on cell metastasis. The mechanisms underlying the action of Id2 were investigated using RNA-seq and pathway analyses. Furthermore, the correlations of Id2 with its target gene expression and clinical outcomes were calculated. Results: Our data revealed that Id2 overexpression could inhibit LADC cells' migratory, invasive, proliferation, and colony formation capabilities. Silencing Id2 expression in LADC cells reversed the aforementioned inhibitory effects, and knockdown of Id2 increased LADC cells' metastatic abilities in vivo. Bioinformatics analysis revealed that these effects of Id2 on cancer progression might be regulated by focal adhesion kinase (FAK) signaling and CD44/Twist expression. Furthermore, in online clinical database analysis, patients with LADC whose Id2 expression levels were high and FAK/Twist expression levels were low had superior clinical outcomes.Conclusion: Our data indicate that the Id2 gene may act as a metastasis suppressor and provide new insights into LADC progression and therapy.

HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages.

Heat shock protein (HSP) 40 has emerged as a key factor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin-induced sepsis severity is still unclear. During lipopolysaccharide (LPS)-induced endotoxic shock, HLJ1 knockout mice shows reduced organ injury and IFN-γ (interferon-γ)-dependent mortality. Using single-cell RNA sequencing, we characterize mouse liver nonparenchymal cell populations under LPS stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. In CLP models, HLJ1 deletion reduces IFN-γ expression and sepsis mortality rate when mice are treated with antibiotics. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4+ or CD8+ T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ-dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ-dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activated IL-12/IFN-γ axis.

PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients.

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.

The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small cell lung cancer. OBJECTIVE: The main objective of the present study was to compare the clinical efficacies between osimertinib and afatinib as first-line treatment in patients with EGFR-mutant non-small cell lung cancer. METHODS: We retrospectively analyzed patients with advanced and recurrent non-small cell lung cancer who harbored an exon 19 deletion or an exon 21 L858R mutation and were being given either osimertinib or afatinib as first-line treatment from January 2018 to December 2020. RESULTS: A total of 128 patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median follow-up time was 20.1 months in the osimertinib group and 22.7 months in the afatinib group. The median progression-free survival was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (hazard ratio 0.75 [95% confidence interval 0.48-1.18]). The median overall survival was not reached in the osimertinib group and was 41.7 months in the afatinib group (hazard ratio 0.79 [95% confidence interval 0.36-1.72]). In patients without brain metastasis, the median progression-free survival was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (hazard ratio 1.02 [95% confidence interval 0.56-1.85]). In patients with brain metastasis at baseline, the median progression-free survival was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted hazard ratio 0.45 [95% confidence interval 0.21-0.96]). CONCLUSIONS: Our research demonstrates that there was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median progression-free survival and overall survival than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median progression-free survival than afatinib in patients with brain metastasis at baseline.

Hybrid Pharmacophore- and Structure-Based Virtual Screening Pipeline to Identify Novel EGFR Inhibitors That Suppress Non-Small Cell Lung Cancer Cell Growth.

Dysregulated epidermal growth factor receptor (EGFR) expression is frequently observed in non-small cell lung cancer (NSCLC) growth and metastasis. Despite recent successes in the development of tyrosine kinase inhibitors (TKIs), inevitable resistance to TKIs has led to urgent calls for novel EGFR inhibitors. Herein, we report a rational workflow used to identify novel EGFR-TKIs by combining hybrid ligand- and structure-based pharmacophore models. Three types of models were developed in this workflow, including 3D QSAR-, common feature-, and structure-based EGFR-TK domain-containing pharmacophores. A National Cancer Institute (NCI) compound dataset was adopted for multiple-stage pharmacophore-based virtual screening (PBVS) of various pharmacophore models. The six top-scoring compounds were identified through the PBVS pipeline coupled with molecular docking. Among these compounds, NSC609077 exerted a significant inhibitory effect on EGFR activity in gefitinib-resistant H1975 cells, as determined by an enzyme-linked immunosorbent assay (ELISA). Further investigations showed that NSC609077 inhibited the anchorage-dependent growth and migration of lung cancer cells. Furthermore, NSC609077 exerted a suppressive effect on the EGFR/PI3K/AKT pathway in H1975 cells. In conclusion, these findings suggest that hybrid virtual screening may accelerate the development of targeted drugs for lung cancer treatment.

The ACE genes in Aphelenchoides besseyi isolates and their expression correlation to the fenamiphos treatment.

Aphelenchoides besseyi could cause great yield losses of rice and many economically important crops. Acetylcholinesterase (AChE) inhibitors were commonly used to manage plant-parasitic nematodes. However, nematodes resistant to AChE inhibitors have been increasingly reported due to the extensive use of these chemicals. The current study was aimed to establish the correlation between fenamiphos (an AChE-inhibitor) sensitivities and acetylcholinesterase genes (ace) by analyzing two isolates of A. besseyi (designated Rl and HSF), which displayed differential sensitivities to fenamiphos. The concentrations of fenamiphos that led to the death of 50% (LD50) of Rl and HSF were 572.2 ppm and 129.4 ppm, respectively. Three ace genes were cloned from A. besseyi and sequenced. Sequence searching and phylogenic analyses revealed that AChEs of R1 and HSF shared strong similarities with those of various vertebrate and invertebrate species. Molecular docking analysis indicated that AChEs-HSF had much higher affinities to fenamiphos than AChEs-R1. Quantitative reverse transcriptase-PCR analyses revealed that expression of three ace genes were downregulated in HSF but were upregulated in Rl after exposure to 100 ppm fenamiphos for 12 h. The results indicated that the expression of the ace genes was modulated in response to fenamiphos in different nematode strains. An increased expression of the ace genes might contribute to fenamiphos-insensitivity as seen in the Rl isolate.

The Clinical Outcomes of Different First-Line EGFR-TKIs Plus Bevacizumab in Advanced EGFR-Mutant Lung Adenocarcinoma.

PURPOSE: The aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced EGFR-mutant lung adenocarcinoma patients. MATERIALS AND METHODS: From August 2016 to October 2020, we enrolled advanced lung adenocarcinoma patients harboring exon 19 deletion or L858R receiving gefitinib, erlotinib and afatinib plus bevacizumab as the first-line treatment for the purposes of analysis. RESULTS: A total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. The objective response rate was 77.8%, and disease control rate was 94.4%. The overall median progression-free survival (PFS) was 16.4 months, while the median PFS was 17.1 months in patients with exon 19 deletion, and 16.2 months in patients with L858R mutation (p=0.311). Regarding the use of different EGFR-TKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (p=0.617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (p=0.747). Amongst patients harboring exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not-reached in the afatinib group (p=0.141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (p=0.481). CONCLUSION: Our research demonstrates that not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients.

ANA positivity and complement level in pleural fluid are potential diagnostic markers in discriminating lupus pleuritis from pleural effusion of other aetiologies.

OBJECTIVE: Lupus pleuritis is the most common pulmonary manifestation of systemic lupus erythematosus (SLE). We aimed to compare various biomarkers in discriminating between pleural effusions due to lupus pleuritis and other aetiologies. METHODS: We determined in 59 patients (16 patients with SLE and 43 patients without SLE) pleural fluid levels of high-mobility group box 1, soluble receptor for advanced glycation end products (sRAGE), adenosine deaminase (ADA), interleukin (IL) 17A, tumour necrosis factor-α, antinuclear antibodies (ANA), and complements C3 and C4. RESULTS: We found significant differences in the pleural fluid level of sRAGE, ADA, IL-17A, C3 and C4, and in the proportion of ANA positivity, among lupus pleuritis and other groups with pleural effusion. Specifically, ANA positivity (titre ≥1: 80) achieved a high sensitivity of 91%, specificity of 83% and negative predictive value (NPV) of 97% in discriminating lupus pleuritis from non-lupus pleural effusion. A parallel combination of the level of C3 (<24 mg/dL) and C4 (<3 mg/dL) achieved a sensitivity of 82%, specificity of 89% and NPV of 93% in discriminating lupus pleuritis from non-lupus exudative pleural effusion. CONCLUSIONS: In conclusion, ANA, C3 and C4 in pleural fluid are useful in discriminating lupus pleuritis from pleural effusion due to other aetiologies with high NPV.

Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts.

The tumorous niche may drive the plasticity of heterogeneity and cancer stemness, leading to drug resistance and metastasis, which is the main reason of treatment failure in most cancer patients. The aim of this study was to establish a tumor microenvironment (TME)-based screening to identify drugs that can specifically target cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) in the TME. Methods: Lung cancer patient-derived cancer cell and CAFs were utilized to mimic the TME and reproduce the stemness properties of CSCs in vitro and develop a high-throughput drug screening platform with phenotypical parameters. Limiting dilution assay, sphere-forming and ALDH activity assay were utilized to measure the cancer stemness characteristics. In vivo patient-derived xenograft (PDX) models and single-cell RNA sequencing were used to evaluate the mechanisms of the compounds in CSCs and CAFs. Results: The TME-based drug screening platform could comprehensively evaluate the response of cancer cells, CSCs and CAFs to different treatments. Among the 1,524 compounds tested, several drugs were identified to have anti-CAFs, anticancer and anti-CSCs activities. Aloe-emodin and digoxin both show anticancer and anti-CSCs activity in vitro and in vivo, which was further confirmed in the lung cancer PDX model. The combination of digoxin and chemotherapy improved therapeutic efficacy. The single-cell transcriptomics analysis revealed that digoxin could suppress the CSCs subpopulation in CAFs-cocultured cancer cells and cytokine production in CAFs. Conclusions: The TME-based drug screening platform provides a tool to identify and repurpose compounds targeting cancer cells, CSCs and CAFs, which may accelerate drug development and therapeutic application for lung cancer patients.

The impact of different first-line EGFR-TKIs on the clinical outcome of sequential osimertinib treatment in advanced NSCLC with secondary T790M.

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.

Primary Tumor Radiotherapy During EGFR-TKI Disease Control Improves Survival of Treatment Naïve Advanced EGFR-Mutant Lung Adenocarcinoma Patients.

BACKGROUND: Whether radiotherapy only for primary lung tumor (RTPLT) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy improves survival of treatment naïve advanced EGFR-mutant lung adenocarcinoma (LAD) patients with/without polymetastasis. MATERIALS AND METHODS: This was a retrospective, single-center, observational study. Patients with stage IIIB-IV EGFR-mutant LAD with disease control by EGFR-TKI therapy were divided into curative RTPLT, and control, without radiotherapy (WRTPLT) groups. RESULTS: A total of 138 patients were enrolled; 46 in the RTPLT group and 92 in the WRTPLT group. Amongst them, 37% had oligometastasis, and 26.1% brain metastasis. The RTPLT group had both significantly longer progression-free survival (PFS) (27.5 months [95% CI 18.1-36.9] vs 10.9 months [95% CI 6.3-15.5], P<0.001) and overall survivor (OS) (NR [95% CI NR-NR] vs 38.0 months [95% CI 31.2-44.8], P<0.001), respectively, when compared to the WRTPLT group. In multivariate analysis, the adjusted HR of radiotherapy on PFS was 0.30 (0.19-0.47) and on OS, 0.11 (0.04-0.30). Patients with oligometastasis had significantly longer PFS than those with polymetastasis with an HR of 0.35 (0.14-0.85), P=0.02. Patients with either oligometastasis or polymetastasis had significant longer PFS when undergoing radiotherapy than those without (both P<0.05). An EGFR-TKI to radiotherapy interval <24 weeks seemed more beneficial (P=0.097). Radiation pneumonitis comprised 32 (69.6%), 12 (26.1%), and two (4.3%) cases of common terminology criteria grade I, II, and III, respectively. CONCLUSION: Curative RTPLT can prolong survival in patients with LAD following EGFR-TKI disease control, both involving oligometastasis and polymetastasis. RTPLT within 24 weeks after EGFR-TKI initiation appeared to be more beneficial with tolerable radiation pneumonitis.

MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role.

Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of ß-tubulin.

Developing new therapeutic strategies to overcome drug resistance of cancer cells is an ongoing endeavor. From among 2 million chemicals, we identified ethyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (AS1712) as a low-toxicity inhibitor of lung cancer cell proliferation and xenograft tumor growth. We show that AS1712 is active against broad cancer cell lines and is able to bind in the colchicine-binding pocket of ß-tubulin, thereby inhibiting microtubule assembly and, consequently, inducing mitotic arrest and apoptosis. Our cell-based structure-activity relationship study identified a new lead compound, RJ-LC-15-8, which had a greater anti-proliferative potency for H1975 cells than did AS1712, while maintaining a similar mechanism of action. Notably, AS1712 and RJ-LC-15-8 overcame P-glycoprotein efflux pump and ß-tubulin alterations that lead to acquired resistance against microtubule-targeting drugs of cancer cells. AS1712 and RJ-LC-15-8 may be lead compounds that overcome acquired resistance to microtubule-targeting agents of cancer cells.

High PD-L1 expression correlates with primary resistance to EGFR-TKIs in treatment naïve advanced EGFR-mutant lung adenocarcinoma patients.

OBJECTIVES: The main objective was to investigate the relationship between Programmed cell Death-ligand 1 (PD-L1) expression levels and the frequency of primary resistance to Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor (TKI) in treatment naïve advanced EGFR-mutant lung adenocarcinoma patients. MATERIALS AND METHODS: From 2012-2017, we enrolled advanced EGFR-mutant lung adenocarcinoma patients who displayed primary resistance to EGFR-TKI therapy, along with patients with disease control, and patients experiencing either stable disease or partial response to EGFR-TKI treatment. RESULTS: Sixty-six patients were enrolled as the primary resistance group, while 57 patients were included as the disease control group. Fifteen-five (22.7%) patients had a PD-L1 Tumor Proportion Score (TPS) ≧50% in the primary resistance group, with only one patient (1.8%) having that score in the disease control group (P＜0.001). Twenty (30.3%) patients had a PD-L1 ≧25% in the primary resistance group, with 2 (3.5%) patients having that level in the disease control group (P＜0.001). Thirty (45.5%) patients had a PD-L1 ≧1% in the primary resistance group, with 7 (12.3%) patients at that level in the disease control group (P = 0.001). Patients with a PD-L1≧1% displayed a higher incidence of primary resistance to EGFR-TKIs than those with a PD-L1＜1% (Odds Ratio (OR), 5.95; 95% Confidence Interval (CI), 2.35-15.05; P＜0.001). The phenomenon existed still when the cutoff value was changed to both 25% (OR, 11.96; 95% CI, 2.65-53.87; P = 0.001) and 50% (OR, 16.47; 95% CI, 2.10-129.16; P = 0.008). The estimated median Progression-free Survival (PFS) rate was 7.3 months in patients with a PD-L1＜1%, 2.1 months in patients with a PD-L1≧1%, 1.8 months in patients with a PD-L1≧25%, and 1.6 months in patients with a PD-L1≧50%. CONCLUSIONS: Treatment for advanced EGFR-mutant lung adenocarcinoma patients displaying a higher PD-L1 expression level experienced a higher frequency of primary resistance to EGFR-TKIs.