High-fat diet induces C-reactive protein secretion, promoting lung adenocarcinoma via immune microenvironment modulation.

To understand the effects of a high-fat diet (HFD) on lung cancer progression and biomarkers, we here used an inducible mutant epidermal growth factor receptor (EGFR)-driven lung cancer transgenic mouse model fed a regular diet (RD) or HFD. The HFD lung cancer (LC-HFD) group exhibited significant tumor formation and deterioration, such as higher EGFR activity and proliferation marker expression, compared with the RD lung cancer (LC-RD) group. Transcriptomic analysis of the lung tissues revealed that the significantly changed genes in the LC-HFD group were highly enriched in immune-related signaling pathways, suggesting that an HFD alters the immune microenvironment to promote tumor growth. Cytokine and adipokine arrays combined with a comprehensive analysis using meta-database software indicated upregulation of C-reactive protein (CRP) in the LC-HFD group, which presented with increased lung cancer proliferation and metastasis; this was confirmed experimentally. Our results imply that an HFD can turn the tumor growth environment into an immune-related pro-tumorigenic microenvironment and demonstrate that CRP has a role in promoting lung cancer development in this microenvironment.

Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.

OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

MiR-503 pleiotropically regulates epithelial-mesenchymal transition and targets PTK7 to control lung cancer metastasis.

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.

LCRMP-1 is required for spermatogenesis and stabilises spermatid F-actin organization via the PI3K-Akt pathway.

Long-form collapsin response mediator protein-1 (LCRMP-1) belongs to the CRMP family which comprises brain-enriched proteins responsible for axon guidance. However, its role in spermatogenesis remains unclear. Here we find that LCRMP-1 is abundantly expressed in the testis. To characterize its physiological function, we generate LCRMP-1-deficient mice (Lcrmp-1-/-). These mice exhibit aberrant spermiation with apoptotic spermatids, oligospermia, and accumulation of immature testicular cells, contributing to reduced fertility. In the seminiferous epithelial cycle, LCRMP-1 expression pattern varies in a stage-dependent manner. LCRMP-1 is highly expressed in spermatids during spermatogenesis and especially localized to the spermiation machinery during spermiation. Mechanistically, LCRMP-1 deficiency causes disorganized F-actin due to unbalanced signaling of F-actin dynamics through upregulated PI3K-Akt-mTOR signaling. In conclusion, LCRMP-1 maintains spermatogenesis homeostasis by modulating cytoskeleton remodeling for spermatozoa release.

Senomorphic effect of diphenyleneiodonium through AMPK/MFF/DRP1 mediated mitochondrial fission.

With an aging population and the numerous health impacts associated with old age, the identification of anti-aging drugs has become an important new research direction. Although mitochondria have been recognized to affect aging, anti-aging drugs specifically targeting the mitochondria are less well characterized. In this study, diphenyleneiodonium (DPI) was identified as a potential senomorphic drug that functions by promoting mitochondrial fission. DPI significantly reduced the number of senescence-associated ß-galactosidase (SA-ß-gal) positive cells and increased the number of proliferating Ki-67 positive cells in BrdU or irradiation stress-induced senescent NIH3T3 cells or IMR90 cells and mouse embryonic fibroblasts (MEFs) replicative senescent cells. Cell cycle arrest genes and senescence-associated secretory phenotype (SASP) factors were downregulated with DPI treatment. In addition, the oxygen consumption rate (OCR) of mitochondrial respiration showed that DPI significantly reduced senescence-associated hyper OCR. Mechanistically, DPI promoted mitochondrial fission by enhancing AMPK/MFF phosphorylation and DRP1 mitochondrial translocation. Inhibition of DRP1 by Mdivi-1 abolished DPI-induced mitochondrial fission and the anti-senescence phenotype. Importantly, Eighty-eight-week-old mice treated with DPI had significantly reduced numbers of SA-ß-gal positive cells and reduced expression of cell cycle arrest genes and SASP factors in their livers and kidneys. Pathological and functional assays showed DPI treatment not only reduced liver fibrosis and immune cell infiltration but also improved aged-related physical impairments in aged mice. Taken together, our study identified a potential anti-aging compound that exerts its effects through modulation of mitochondrial morphology.

Tissue Proteogenomic Landscape Reveals the Role of Uncharacterized SEL1L3 in Progression and Immunotherapy Response in Lung Adenocarcinoma.

The fundamental pursuit to complete the human proteome atlas and the unmet clinical needs in lung adenocarcinoma have prompted us to study the functional role of uncharacterized proteins and explore their implications in cancer biology. In this study, we characterized SEL1L3, a previously uncharacterized protein encoded from chromosome 4 as a dysregulated protein in lung adenocarcinoma from the large-scale tissue proteogenomics data set established using the cohort of Taiwan Cancer Moonshot. SEL1L3 was expressed in abundance in the tumor parts compared with paired adjacent normal tissues in 90% of the lung adenocarcinoma patients in our cohorts. Moreover, survival analysis revealed the association of SEL1L3 with better clinical outcomes. Intriguingly, silencing of SEL1L3 imposed a reduction in cell viability and activation of ER stress response pathways, indicating a role of SEL1L3 in the regulation of cell stress. Furthermore, the immune profiles of patients with higher SEL1L3 expression were corroborated with its active role in immunophenotype and favorable clinical outcomes in lung adenocarcinoma. Taken together, our study revealed that SEL1L3 might play a vital role in the regulation of cell stress, interaction with cancer cells and the immune microenvironment. Our research findings provide promising insights for further investigation of its molecular signaling network and also suggest SEL1L3 as a potential emerging adjuvant for immunotherapy in lung adenocarcinoma.

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.

Various impacts of driver mutations on the PD-L1 expression of NSCLC.

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.

Influence of the Timing of Leptomeningeal Metastasis on the Outcome of EGFR-Mutant Lung Adenocarcinoma Patients and Predictors of Detectable EGFR Mutations in Cerebrospinal Fluid.

BACKGROUND: We aim to evaluate the influence of the timing of leptomeningeal metastasis (LM) occurrence on the outcome of EGFR-mutant lung adenocarcinoma and to explore the predictors of detectable EGFR mutation in the cerebrospinal fluid (CSF). METHODS: EGFR-mutant lung adenocarcinoma patients with cytologically confirmed LM were included for analysis. EGFR mutation in CSF was detected by MALDI-TOF MS plus PNA. RESULTS: A total of 43 patients was analyzed. Of them, 8 (18.6%) were diagnosed with LM prior to first-line EGFR-TKI treatment (early onset), while 35 patients (81.4%) developed LM after first-line EGFR-TKI treatment (late onset). Multivariate analysis suggested that both late-onset LM (aHR 0.31 (95% CI 0.10-0.94), p = 0.038) and a history of third-generation EGFR-TKI treatment (aHR 0.24 (95% CI 0.09-0.67), p = 0.006) independently predicted a favorable outcome. EGFR mutation detection sensitivity in CSF was 81.4%. The radiological burden of LM significantly correlated with CSF tumor cell counts (p = 0.013) with higher CSF tumor cell counts predicting a higher detection sensitivity of EGFR mutation (p = 0.042). CONCLUSIONS: Early onset LM was an independently poor prognostic factor. A higher radiological severity score of LM could predict higher tumor cell counts in CSF, which in turn were associated with a higher detection rate of EGFR mutation.

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.

Uracil-DNA Glycosylase Assay by Matrix-assisted Laser Desorption/Ionization Time-of-flight Mass Spectrometry Analysis.

Uracil-DNA glycosylase (UDG) is a key component in the base excision repair pathway for the correction of uracil formed from hydrolytic deamination of cytosine. Thus, it is crucial for genome integrity maintenance. A highly specific, non-labeled, non-radio-isotopic method was developed to measure UDG activity. A synthetic DNA duplex containing a site-specific uracil was cleaved by UDG and then subjected to Matrix-assisted Laser Desorption/Ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis. A protocol was established to preserve the apurinic/apyrimidinic site (AP) product in DNA without strand break. The change in the m/z value from the substrate to the product was used to evaluate uracil hydrolysis by UDG. A G:U substrate was used for UDG kinetic analysis yielding the Km = 50 nM, Vmax = 0.98 nM/s, and Kcat = 9.31 s-1. Application of this method to a uracil glycosylase inhibitor (UGI) assay yielded an IC50 value of 7.6 pM. The UDG specificity using uracil at various positions within single-stranded and double-stranded DNA substrates demonstrated different cleavage efficiencies. Thus, this simple, rapid, and versatile MALDI-TOF MS method could be an excellent reference method for various monofunctional DNA glycosylases. It also has the potential as a tool for DNA glycosylase inhibitor screening.

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.

Novel Genetic Prognostic Signature for Lung Adenocarcinoma Identified by Differences in Gene Expression Profiles of Low- and High-Grade Histological Subtypes.

The 2021 WHO classification proposed a pattern-based grading system for early-stage invasive non-mucinous lung adenocarcinoma. Lung adenocarcinomas with high-grade patterns have poorer outcomes than those with lepidic-predominant patterns. This study aimed to establish genetic prognostic signatures by comparing differences in gene expression profiles between low- and high-grade adenocarcinomas. Twenty-six (9 low- and 17 high-grade adenocarcinomas) patients with histologically "near-pure" patterns (predominant pattern comprising >70% of tumor areas) were selected retrospectively. Using RNA sequencing, gene expression profiles between the low- and high-grade groups were analyzed, and genes with significantly different expression levels between these two groups were selected for genetic prognostic signatures. In total, 196 significant candidate genes (164 upregulated and 32 upregulated in the high- and low-grade groups, respectively) were identified. After intersection with The Cancer Genome Atlas-Lung Adenocarcinoma prognostic genes, three genes, exonuclease 1 (EXO1), family with sequence similarity 83, member A (FAM83A), and disks large-associated protein 5 (DLGAP5), were identified as prognostic gene signatures. Two independent cohorts were used for validation, and the areas under the time-dependent receiver operating characteristic were 0.784 and 0.703 in the GSE31210 and GSE30219 cohorts, respectively. Our result showed the feasibility and accuracy of this novel three-gene prognostic signature for predicting the clinical outcomes of lung adenocarcinoma.

Genetic Deletion of HLJ1 Does Not Affect Blood Coagulation in Mice.

HLJ1 (also called DNAJB4) is a member of the DNAJ/Hsp40 family and plays an important role in regulating protein folding and activity. However, there is little information about the role of HLJ1 in the regulation of physiological function. In this study, we investigated the role of HLJ1 in blood coagulation using wild-type C57BL/6 mice and HLJ1-null (HLJ1-/-) mice. Western blot analysis and immunohistochemistry were used to assess the expression and distribution of HLJ1 protein, respectively. The tail bleeding assay was applied to assess the bleeding time and blood loss. A coagulation test was used for measuring the activity of extrinsic, intrinsic and common coagulation pathways. Thromboelastography was used to measure the coagulation parameters in the progression of blood clot formation. The results showed that HLJ1 was detectable in plasma and bone marrow. The distribution of HLJ1 was co-localized with CD41, the marker of platelets and megakaryocytes. However, genetic deletion of HLJ1 did not alter blood loss and the activity of extrinsic and intrinsic coagulation pathways, as well as blood clot formation, compared to wild-type mice. Collectively, these findings suggest that, although HLJ1 appears in megakaryocytes and platelets, it may not play a role in the function of blood coagulation under normal physiological conditions.

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.

Prognostic Characteristics and Immunotherapy Response of Patients With Nonsquamous NSCLC With Kras Mutation in East Asian Populations: A Single-Center Cohort Study in Taiwan.

INTRODUCTION: Kras mutation is the most common driver oncogene present in patients with NSCLC. Recently, the precision medicine for patients with Kras-mutated NSCLC has been under investigation, but the best treatment is still unknown. This study aimed to analyze the clinical characteristics, immune checkpoint inhibitor (ICI) response, and prognostic factors of patients with NSCLC with different Kras mutation subtypes. METHODS: From 2005 to 2018, we collected nonsquamous NSCLC tissue samples for Kras mutation analysis using direct Sanger sequencing or MassARRAY genotyping (Agena Bioscience, San Diego, CA) at the National Taiwan University Hospital. Clinical characteristics, ICI treatment effectiveness, time-to-tumor recurrence (TTR), and overall survival (OS) were analyzed using multivariate Cox models, to estimate adjusted hazard ratios (HRs). RESULTS: Among 5278 patients with nonsquamous NSCLC, 246 (4.7%) had Kras mutations. The major Kras mutation subtypes were G12C (32.9%), G12D (23.7%), and G12V (18.9%). Patients with Kras-G12C had a higher proportion of male individuals (p = 0.018) and smokers (p < 0.001). Among the 25 patients treated with ICIs, patients with Kras-G12C had a higher response rate (53.8% versus 8.3%, p = 0.030) and longer progression-free survival (4.8 mo versus 2.1 mo, p = 0.028) than those with Kras-non-G12C. For the 85 patients with early-stage NSCLC, those with G12C had shorter TTR (22.8 mo) than those with Kras-non-G12C (97.7 mo, p = 0.004). For the 143 patients with advanced-stage NSCLC, there was a significant difference in OS between patients with Kras-G12C and Kras-non-G12C (7.7 mo versus 6.0 mo, p = 0.018) and patients with Kras-G12V had the shortest OS (5.2 mo). Multivariate analysis revealed association of shorter OS with Kras-G12V (HR = 2.47, p = 0.002), stage IV disease status (HR = 2.69, p = 0.008), and NSCLC-not otherwise specified histology (HR = 3.12, p = 0.002). CONCLUSIONS: Kras-G12C was associated with favorable ICI treatment effectiveness in patients with NSCLC. Kras-G12C mutation was associated with shorter TTR in patients with early-stage NSCLC, and Kras-G12V mutation was associated with shorter OS in patients with advanced-stage NSCLC when comparing with Kras-G12C.

Transthyretin as a Biomarker to Predict and Monitor Major Depressive Disorder Identified by Whole-Genome Transcriptomic Analysis in Mouse Models.

BACKGROUND: Accumulations of stressful life events result in the onset of major depressive disorder (MDD). Comprehensive genomic analysis is required to elucidate pathophysiological changes and identify applicable biomarkers. METHODS: Transcriptomic analysis was performed on different brain parts of a chronic mild stress (CMS)-induced MDD mouse model followed by systemic analysis. QPCR and ELISA were utilized for validation in mice and patients. RESULTS: The highest numbers of genes with significant changes induced by CMS were 505 in the amygdala followed by 272 in the hippocampus (twofold changes; FDR, p < 0.05). Enrichment analysis indicated that the core-enriched genes in CMS-treated mice were positively enriched for IFN-γ response genes in the amygdala, and hedgehog signaling in the hippocampus. Transthyretin (TTR) was severely reduced in CMS-treated mice. In patients with diagnosed MDD, serum concentrations of TTR were reduced by 48.7% compared to controls (p = 0.0102). Paired samples from patients with MDD demonstrated a further 66.3% increase in TTR at remission compared to the acute phase (p = 0.0339). CONCLUSIONS: This study provides comprehensive information on molecular networks related to MDD as a basis for further investigation and identifies TTR for MDD monitoring and management. A clinical trial with bigger patient cohort should be conducted to validate this translational study.

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.