Neoangiogenesis is crucial for sustained tumour growth and metastasis. Vascular endothelial growth factor(VEGF) plays the most role in regulation of neoangiogenesis. Moreover,members of the VEGF family are in volved in different biological processes. Much progress has been achieved inelucidating its signal transduction. It is now well established that VEGF axis represents an important target for antitumor especially in therapy of non-small cell lung cancer.
Key words:
Vascular endothelial growth factor; Receptor; Non-small cell lung cancer; Angiogenesis inhibitor
Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at molecular level. Circulating tumor DNA (ctDNA), validated as a tool for mutation detection in lung cancer, could reflect dynamic molecular changes. We evaluated the utility of ctDNA as a predictive and a prognostic marker in disease monitoring of advanced non-small cell lung cancer (NSCLC) patients. Methods: This is a multicenter prospective cohort study. We performed capture-based ultra-deep sequencing on longitudinal plasma samples utilizing a panel consisting of 168 NSCLC-related genes on 949 advanced NSCLC patients with driver mutations to monitor treatment responses and disease progression. The correlations between ctDNA and progression-free survival (PFS)/overall survival (OS) were performed on 248 patients undergoing various treatments with the minimum of 2 ctDNA tests. Results: The results of this study revealed that higher ctDNA abundance (P=0.012) and mutation count (P=8.5×10−4) at baseline are associated with shorter OS. We also found that patients with ctDNA clearance, not just driver mutation clearance, at any point during the course of treatment were associated with longer PFS (P=2.2×10−16, HR 0.28) and OS (P=4.5×10−6, HR 0.19) regardless of type of treatment and evaluation schedule. Conclusions: This prospective real-world study shows that ctDNA clearance during treatment may serve as predictive and prognostic marker across a wide spectrum of treatment regimens.
Tumor inflammatory microenvironment is considered to play the role in the sensitivity of tumor cells to therapies and prognosis of lung cancer patients. Interleukin-8 (IL-8) is one of critical chemo-attractants responsible for leukocyte recruitment, cancer proliferation, and angiogenesis. The present study aimed at investigating potential mechanism of IL-8 production from human non-small cell lung cancer (NSCLC) SPC-A1 cells. We initially found that EGF could directly stimulate IL-8 production, proliferation, and bio-behaviors of lung cancer cells through the activation of EGFR, PI3K, Akt, and Erk signal pathway. EGF-stimulated IL-8 production, phosphorylation of Akt and Erk, and cell proliferation and movement could be inhibited by EGFR inhibitor (Erlotinib), PI3K inhibitor (GDC-0941 BEZ-235 and SHBM1009), and ERK1/2 inhibitor (PD98059). Our data indicate that IL-8 production from lung cancer cells could be initiated by their own produced factors, leading to the recruitment of inflammatory cells in the cancer tissue, and the formation of inflammatory microenvironment. Thus, it seems that the signal pathway of EGFR-PI3K-Akt-Erk can be the potential target of therapies for inflammatory microenvironment in lung cancer.
Objective:To improve the diagnosis of lymphamas in FUO cases. Methods:Three patients with lymphomas and FUO confirmed by pathology were presented and the relevant literatures were reviewed.Also,laboratory tests,invasive and non-invasive procedures were analysed. Results:18F-FDG PET imaging appears to be a valuable imaging procedure for screening of lymphoma in FUO cases. Lymph nodes biopsy,bone marrow examination and spleen needle biopsy are helpful to identify the disease. Conclusion:The clinical features of lymphomas in FUO cases are insufficient to characterise a disease,and they may be misdiagnosized. Biopsy may then confirm the diagnosis.
Abstract RNA splicing dysregulation is a hallmark of cancers and underlies the onset and progression of diseases. Chronic lymphocytic leukemia (CLL) is one of the most common adult leukemia in western countries. Spliceosome mutations occur in ~20% of patients. However, the mechanism for splicing defects in spliceosome unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis of primary CLL samples, we discovered proteins involved in RNA splicing are post-transcriptionally upregulated. Coupled with clinical annotation, we found spliceosome protein abundance is an independent risk factor and associated with poor prognosis. Splice variants found in CLL are highly overlapped with those driven by high spliceosome abundance but not splicing factor mutations, indicating high spliceosome abundance contributes to genetic lesion-independent splicing defects. To identify potential regulators for spliceosome, we proteome-widely analyzed the proteins that highly correlated with splicing factors expression. Analysis of 113 CLL samples has consistently identified METTL3 upregulation with positive correlation with 77.6% of detected splicing factors. METTL3 is an RNA methyltransferase that modifies N6-methyladenosine (m6A) on mRNA and regulates the translation of m6A-installed transcripts. m6A level on mRNA is increased in CLL cells with differential m6A highly enriched on splicing related transcripts. Moreover, high METTL3 expression in CLL is also associated with poor clinical outcomes. These results suggested that METTL3 translationally controls splicing factors through m6A and plays a role in CLL progression. Toward this end, we demonstrated that METTL3 is essential for CLL growth in both in vitro and in vivo studies. Knock out (KO) and pharmaceutical inhibition of METTL3 decreased cell growth and splicing factor expression. Overexpression of wildtype but not catalytic mutant METTL3 restored both defects in METTL3 KO cells, indicating that the regulation of splicing factor is m6A-dependent. To dissect the underlying mechanism, we performed an integrated Ribo-seq, RNA-seq, and MeRIP-seq on CLL cells with or without METTL3. KO of METTL3 decreased overall translation efficiency (TE) with RNA splicing as the most significantly affected pathway. Splicing factors with reduced TE displayed either hypo-m6A at stop codon region or hyper-m6A at CDS regions upon METTL3 KO, as direct or indirect targets of METTL3. Moreover, we found that m6A at stop codon and CDS regions regulates splicing factor translation via ribosome recycling and ribosome pausing, respectively. Taken together, our results uncovered a novel regulatory axis for METTL3 that controls splicing factor translation and contributes to CLL progression. Our study highlights a post-transcriptional layer of m6A modification as a major contributor to genetic lesion-independent splicing defects in CLL. Citation Format: Yiming Wu, Meiling Jin, Mike Fernandez, Kevyn Hart, Aijun Liao, Stacey M. Fernandes, Tinisha McDonald, Zhenhua Chen, Daniel Röth, Lucy Ghoda, Guido Marcucci, Markus Kalkum, Raju K. Pillai, Alexey V. Danilov, Jianjun Chen, Jennifer R. Brown, Steven T. Rosen, Tanya Siddiqi, Lili Wang. METTL3-mediated m6A modification controls splicing factor abundance and contributes to CLL progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3482.
Indirect immunoperoxidase staining technique using frozen sections of adult worm as antigen (IIP-AWA) was carried out to detect antibodies against schistosome antigens (AWAb) for the diagnosis of existing infection of schistosomiasis in COPT positive cases. Sera from 229 COPT positive and 135 COPT negative cases in Shanghai County, where schistosomiasis had been eradicated for more than 5 years, were tested. Sera from 122 patients with positive stool hatching from an endemic area were served as positive controls. The positive rates of the three groups were 96.9%, 5.2%, and 100% respectively. The staining pattern of the worm sections was mainly diffused at serum dilutions 1:4 to 1:16. 149 sero-positive cases were treated with pyquiton (60 mg/kg.2d) and re-examined 1, 1.5, and 2.5 years post-treatment. The negative conversion rate of IIP-AWA was considerably higher than that of COPT (80% vs. 61.1%) at the first year, but no significant difference was observed after 2.5 years (85.5% vs. 83.6%). With the decreasing antibody titer, the staining pattern of worm sections changed from diffused to focal pattern, mostly in the gut. The results suggest that the presence of detectable AWAb in untreated patients or patients treated 2 years ago with pyquiton possibly indicate latent schistosomiasis. IIP-AWA is of practical value in screening populations for latent schistosomiasis in areas where the disease had been under control.
Particulate matter (PM) exposure is identified as a critical risk factor for chronic airway diseases, but the biological mechanism of PM-induced lung damage was not fully elucidated. The m6A methylation, as the main member of epigenetic modifications, has been found to play an important role in different pulmonary diseases, but its regulatory effect on PM-induced lung damage remains unknown. This study firstly used the methylated RNA immunoprecipitation sequencing (MeRIP-seq) to reveal the m6A methylome profiles in the lung tissues of mice with acute PM exposure. Compared with the normal control, a total of 2210 differentially hypermethylated m6A peaks within 1879 genes and 1278 differentially hypomethylated m6A peaks within 1153 genes were identified in the PM-exposed group. Conjoint analysis of MeRIP-seq and high-throughput sequencing for RNA (RNA-seq) data predicated several potential pathways including MAPK signaling pathway, cell senescence, and cell cycle. Four m6A-modified differentially expressed genes (IL-1a, IL-1b, ADAM-8, and HMOX-1) were selected for validation using MeRIP-qPCR. Furthermore, the m6A-modified IL-1a promoted PM-induced inflammation via regulating MAPK signaling pathway. These results provide a new insight into the biological mechanism of PM-induced lung damage, and help us to develop new methods to prevent and treat PM-induced adverse health effects.
Abstract Background: Lymphangioleiomyomatosis (LAM) is a multisystem disease that mainly presents with cystic damage in the lungs. The purpose of this study was to quantify the degree of pulmonary cystic damage in CT and to compare its correlation with pulmonary function tests (PFTs) and serum levels of vascular endothelial growth factor (VEGF-D). Subjects and methods: 21 patients were included and 36 CT scans and PFTs were analyzed. The correlation of serum VEGF-D levels of 17 patients and their 24 CT scans were studied. Cystic areas were identified by the software. The volumetric percentage of cystic regions of the total lung volume was calculated to get a cyst score. A ROC curve was calculated to select the threshold at which the cyst scores could predict the lung impairment best. Results: The cyst scores correlated best with FEV1%pred (r = -0.72, p<0.01) and DLCO%pred (r = -0.82, p<0.01). The correlation with serum VEGF-D levels (r = -0.143, p = 0.506) was not obvious. The Youden Index is max (0.667) when cyst score is 15.80%. Conclusion: The pulmonary cyst scores on CT is strongly correlated with FEV1%pred and DLCO%pred. However, the association with serum levels of VEGF-D is not obvious. Cyst score >15.80% might indicate an abnormal lung function and patients are recommended a sirolimus treatment.
With a pair of primers designed to amplify flagellin gene of Bordetella bronchiseptica according to the upstream sequence of the gene,a fragment of 237 bp in length of the target gene was amplified by PCR and a standard PCR assay was developed for quick detection of B.bronchiseptica infection.Specificity and sensitivity assays revealed that the assay did not cross react with Escherichia coli,Staphylococcus aureus and Pasteurella multocida type D,and the assay could detect as low as 112.5pg template DNA.48 samples of nasal mucus from pigs from Yanbian Prefecture with different clinical symptoms was examined by the developed PCR assay and 42 samples(87.5%) were positive.Comparison of the assay with the conventional bacterioscopy and the micro-agglutination test revealed that the sensitivity of the PCR assay was 5.25 times higher than that of the bacterioscopy and 1.75 times higher than that of the micro-agglutination test.
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