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Background: The Lung Immune Prognostic Index (LIPI) combines the lactate dehydrogenase (LDH) level and the derived neutrophil-to-lymphocyte ratio (dNLR). A lot of studies have shown that LDH and dNLR are associated with the prognosis of advanced non-small cell lung cancer (NSCLC) in patients treated with programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors. However, previous results were inconsistent, and the conclusions remain unclear. This meta-analysis aimed to investigate the predictive value of pretreatment LDH and dNLR for NSCLC progression in patients treated with PD-1/PD-L1 inhibitors. Methods: PubMed, Embase, and the Cochrane Library were searched by two researchers independently for related literature before March 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) were extracted to assess the predictive value of LDH and dNLR. STATA 15. 0 was used to perform the meta-analysis. Results: A total of 3,429 patients from 26 studies were included in this meta-analysis. The results revealed that high pretreatment LDH was related to poor OS (HR = 1.19, 95%CI = 1.11–1.24, p < 0.001), but not closely related to poor PFS (HR = 1.02, 95%CI = 1.00–1.04, p = 0.023 < 0.05). The pooled results for dNLR suggested that high pretreatment dNLR was related to poor OS (HR = 1.55, 95%CI = 1.33–1.80, p < 0.001) and PFS (HR = 1.33, 95%CI = 1.16–1.54, p < 0.001). Conclusion: Both pretreatment LDH and dNLR have the potential to serve as peripheral blood biomarkers for patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors. However, more studies on LDH are needed to evaluate its predictive value for PFS in patients with NSCLC. [ABSTRACT FROM AUTHOR]

The basic helix-loop-helix (bHLH) transcription factors are negatively regulated by inhibitor of DNA-binding (ID) proteins. Several studies have demonstrated that ID family proteins are dysregulated in a variety of cancer types, including in lung adenocarcinoma (LUAD). In current study, the prognostic value of ID family members was evaluated by investigating publicly accessible databases, including Oncomine, Kaplan-Meier plotter, UALCAN and the Human Protein Atlas. It was observed that the mRNA expression of all ID members was downregulated in LUAD tumor tissues compared with those in normal tissues according to the Oncomine and UALCAN databases. Additionally, increased mRNA expression levels of ID2 and ID1 were associated with improved and poorer survival time, respectively. Notably, ID3 and ID4 expression was not associated with survival in patients with LUAD. At the protein level, high ID2 significantly predicted an improved survival outcome while high ID1 is associated with shorter survival time. Thus, the results indicate that the ID proteins, particularly ID2, exhibit significant prognostic value in LUAD. More studies are required to elucidate the underlying molecular mechanisms behind the role of the ID family in the development of LUAD. [ABSTRACT FROM AUTHOR]

Acquired resistance remains a key challenge in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) therapy in lung adenocarcinoma (LUAD). Recent studies have shown that Notch signaling is associated with drug resistance. However, its role and possible mechanisms in EGFR-TKI resistance are not yet clear. In our study, we found that among four members of NOTCH1-4, only NOTCH3 was upregulated in LUAD tissues and TKI-resistant cell line (HCC827GR6). Knockdown of NOTCH3 by siRNA significantly inhibited proliferative ability, and decreased colony and sphere formation in HCC827GR6 cells. Then miR-150 was identified as a posttranscriptional regulator of NOTCH3. Its expression was downregulated in LUAD tissues and negatively correlated with NOTCH3 mRNA. The cell proliferation and IC50 of gefitinib were decreased in HCC827GR6 cells transfected with miR-150 mimic, but was reversed when cotransfected with NOTCH3 overexpressed vector. Moreover, we also enrolled 20 patients with advanced LUAD who have taken TKIs as first-line therapy in this study. We found that collagen 1A1 (COL1A1) expression was increased significantly in LUAD tissues both at mRNA and protein levels, and positively correlated with NOTCH3 expression verified in our data and TCGA data. Univariate survival analysis showed that patients with high protein expression of NOTCH3 or COL1A1 were associated with shorter overall survival (OS). Taken together, these results suggest that miR-150/NOTCH3/COL1A1 axis contributed to EGFR-TKI resistance in LUAD, which provide a potential therapeutic target for LUAD treatment. [ABSTRACT FROM AUTHOR]

A large amount of maternal RNA is deposited in oocytes and is reserved for later development. Control of maternal RNA translation during oocyte maturation has been extensively investigated and its regulatory mechanisms are well documented. However, translational regulation of maternal RNA in early oogenesis is largely unexplored. In this study, we generated zebrafish zar1 mutants that result in early oocyte apoptosis and fully penetrant male development. Loss of p53 suppresses the apoptosis in zar1 mutants and restores oocyte development. zar1 immature ovaries show upregulation of proteins implicated in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).More importantly, loss of Zar1 causes marked upregulation of zona pellucida (ZP) family proteins, while overexpression of ZP proteins in oocytes causes upregulation of stress-related activating transcription factor 3 (atf3), arguing that tightly controlled translation of ZP proteins is essential for ER homeostasis during early oogenesis. Furthermore, Zar1 binds to ZP gene mRNAs and represses their translation. Together, our results indicate that regulation of translational repression and de-repression are essential for precisely controlling protein expression during early oogenesis. [ABSTRACT FROM AUTHOR]

Coronary vessel development is a highly coordinated process during heart formation. Abnormal development and dysfunction of the coronary network are contributory factors in the majority of heart disease. Understanding the molecular mechanisms that regulate coronary vessel formation is crucial for preventing and treating the disease. We report a zebrafish gene-trap vinculin b (vclb) mutant that displays abnormal coronary vessel development among multiple cardiac defects. The mutant shows overproliferation of epicardium-derived cells and disorganization of coronary vessels, and they eventually die off at juvenile stages. Mechanistically, Vclb deficiency results in the release of another cytoskeletal protein, paxillin, from the Vclb complex and the upregulation of ERK and FAK phosphorylation in epicardium and endocardium, causing disorganization of endothelial cells and pericytes during coronary vessel development. By contrast, cardiac muscle development is relatively normal, probably owing to redundancy with Vcla, a vinculin paralog that is expressed in the myocardium but not epicardium. Together, our results reveal a previously unappreciated function of vinculin in epicardium and endocardium and reinforce the notion that well-balanced FAK activity is essential for coronary vessel development. [ABSTRACT FROM AUTHOR]

Brassica napus is one of the most important oilseed crops in the world. However, there is currently no enough stem transcriptome information and comparative transcriptome analysis of different tissues, which impedes further functional genomics research on B. napus. In this study, the stem transcriptome of B. napus was characterized by RNA-seq technology. Approximately 13.4 Gb high-quality clean reads with an average length of 100 bp were generated and used for comparative transcriptome analysis with the existing transcriptome sequencing data of roots, leaves, flower buds, and immature embryos of B. napus. All the transcripts were annotated against GO and KEGG databases. The common genes in five tissues, differentially expressed genes (DEGs) of the common genes between stems and other tissues, and tissue-specific genes were detected, and the main biochemical activities and pathways implying the common genes, DEGs and tissue-specific genes were investigated. Accordingly, the common transcription factors (TFs) in the five tissues and tissue-specific TFs were identified, and a TFs-based regulation network between TFs and the target genes involved in 'Phenylpropanoid biosynthesis' pathway were constructed to show several important TFs and key nodes in the regulation process. Collectively, this study not only provided an available stem transcriptome resource in B. napus, but also revealed valuable comparative transcriptome information of five tissues of B. napus for future investigation on specific processes, functions and pathways. [ABSTRACT FROM AUTHOR]

Background Although many of the recently approved genomically targeted therapies have improved outcomes for patients in non-small-cell lung cancer (NSCLC) with lung adenocarcinoma, little is known about the genomic alterations that drive lung squamous cell cancer (SCC) and development of effective targeted therapies in lung SCC is a promising area to be further investigated. Discoidin domain receptor 2 (DDR2), is a novel receptor tyrosine kinases that respond to several collagens and involved in tissue repair, primary and metastatic cancer progression. Methods Expression of DDR2 mRNA was analyzed in 54 lung SCC tissues by qRT-PCR. Over-expression approaches were used to investigate the biological functions of DDR2 and its' mutations in lung SCC cells. Conventional Sanger sequencing was used to investigate the mutations of DDR2 gene in 86 samples. The effect of DDR2 and its' mutations on proliferation was evaluated by MTT and colony formation assays; cell migration and invasion was evaluated by trasnwell assays. Lung SCC cells stably transfected with pEGFP-DDR2 WT, pEGFP-DDR2-S131C or empty vector were injection into nude mice to study the effect of DDR2 and its' mutation on tumorigenesis in vivo. Protein and mRNA expression levels of E-cadherin and MMP2 were determined by qRT-PCR and western blot analysis. Differences between groups were tested for significance using Student's t-test (two-tailed). Results In this study, we found that DDR2 mRNA levels were significantly decreased in 54 lung SCC tissues compared with normal lung tissues. Moreover, there were 3 novel DDR2 mutations (G531V, S131C, T681I) in 4 patients and provide the mutation rate of 4.6% in the 86 patients with lung SCC. The mutation of S131C in DDR2 could promote lung SCC cells proliferation, migration and invasion via inducing MMP-2, but reducing E-cadherin expression. Conclusions These data indicated that the novel DDR2 mutation may contribute to the development and progression of lung SCC and this effect may be associated with increased proliferation and invasiveness, at least in part, via regulating E-cadherin expression. [ABSTRACT FROM AUTHOR]

Background: Although many of the recently approved genomically targeted therapies have improved outcomes for patients in non-small-cell lung cancer (NSCLC) with lung adenocarcinoma, little is known about the genomic alterations that drive lung squamous cell cancer (SCC) and development of effective targeted therapies in lung SCC is a promising area to be further investigated. Discoidin domain receptor 2 (DDR2), is a novel receptor tyrosine kinases that respond to several collagens and involved in tissue repair, primary and metastatic cancer progression. Methods: Expression of DDR2 mRNA was analyzed in 54 lung SCC tissues by qRT-PCR. Over-expression approaches were used to investigate the biological functions of DDR2 and its' mutations in lung SCC cells. Conventional Sanger sequencing was used to investigate the mutations of DDR2 gene in 86 samples. The effect of DDR2 and its' mutations on proliferation was evaluated by MTT and colony formation assays; cell migration and invasion was evaluated by trasnwell assays. Lung SCC cells stably transfected with pEGFP-DDR2 WT, pEGFP-DDR2-S131C or empty vector were injection into nude mice to study the effect of DDR2 and its' mutation on tumorigenesis in vivo. Protein and mRNA expression levels of E-cadherin and MMP2 were determined by qRT-PCR and western blot analysis. Differences between groups were tested for significance using Student's t-test (two-tailed). Results: In this study, we found that DDR2 mRNA levels were significantly decreased in 54 lung SCC tissues compared with normal lung tissues. Moreover, there were 3 novel DDR2 mutations (G531V, S131C, T681I) in 4 patients and provide the mutation rate of 4.6% in the 86 patients with lung SCC. The mutation of S131C in DDR2 could promote lung SCC cells proliferation, migration and invasion via inducing MMP-2, but reducing E-cadherin expression. Conclusions: These data indicated that the novel DDR2 mutation may contribute to the development and progression of lung SCC and this effect may be associated with increased proliferation and invasiveness, at least in part, via regulating E-cadherin expression. [ABSTRACT FROM AUTHOR]

Although the correlation between glypican-5 (GPC5) and lung cancer is well known, the effect of GPC5 expression on non-small cell lung cancer (NSCLC) survival remains to be determined. In the present study, GPC5 expression in A549, H3255, and SPC-A1 NSCLC cell lines was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. GPC5 mRNA and protein expression levels were found to be higher in A549 and H3255 cells compared with SPC-A1 cells. The role of GPC5 in NSCLC cell migration was evaluated in vitro by shRNA-mediated knockdown or the overexpression of GPC5 through scratch and transwell assays. The mean migration rates of cancer cells transfected with pRNAT-shRNA-GPC5-1 were reduced compared with the controls in A549 (P<0.001) and H3255 (P=0.001), while the migration rate of SPC-A1 with GPC5 overexpression was higher than that of the control (P=0.001). The downregulation of GPC5 impeded the transmigration of A549 and H3255 while the upregulation of GPC5 expression promoted the transmembrane invasion of SPC-A1. Furthermore, a panel of formalin-fixed paraffin-embedded NSCLC tissues from 127 patients undergoing curative resection (stages I, II and III) between January, 2003 and December, 2008 were obtained in order to investigate the correlation between GPC5 expression and clinicopathological factors using immunohistochemical methods. The results demonstrated that high GPC5 expression levels in NSCLC were associated with respiratory symptoms in lung cancer diagnosis, poor differentiation, vascular invasion, regional lymph node metastasis and a higher TNM stage. Using the Kaplan-Meier method, NSCLC patients with high levels of GPC5 expression demonstrated a significantly shorter overall survival time compared with those with low GPC5 expression levels (median postsurgical survival time: 14.0 months vs. 59.0 months, P=0.001). GPC5 expression was also identified as an independent prognostic factor by Cox regression analysis [adjusted hazard ratio: 2.18; 95% confidence interval (CI): 1.35-3.52; P=0.001]. This study suggested that increased levels of GPC5 expression are a poor prognostic marker for NSCLC. [ABSTRACT FROM AUTHOR]