Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of smallcell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics.cancer diagnostics | personalized therapy A s a genomic disease, cancer involves a series of changes in the genome, starting from primary tumors, via circulating tumor cells (CTCs), to metastases that cause the majority of mortalities (1-3). These genomic alterations include copy number variations (CNVs), single-nucleotide variations (SNVs), and insertions/deletions (INDELs). Regardless of the concentrated efforts in the past decades, the key driving genomic alterations responsible for metastases are still elusive (1).For noninvasive prognosis and diagnosis of cancer, it is desirable to monitor genomic alterations through the circulatory system. Genetic analyses of cell-free DNA fragments in peripheral blood have been reported (4-6) and recently extended to the whole-genome scale (7-9). However, it may be advantageous to analyze CTCs, as they represent intact functional cancer cells circulating in peripheral blood (10). Although previous studies have shown that CTC counting was able to predict progression and overall survival of cancer patients (11,12), genomic analyses of CTCs could provide more pertinent information for personalized therapy (13). However, it is difficult to probe the genomic changes in DNA obtainable from the small number of captured CTCs. To meet this challenge, a single-cell whole-genome amplification (WGA) method, multiple annealing and loopingbased amplification cycles (MALBAC) (14), has been developed to improve the amplification uniformity across the entire genome over previous methods (15,16), allowing precise determination of CNVs and detection of SNVs with a low false-positive rate in a single cell. Here, we present genomic analyses of CTCs from...
Overexpression of complementary DNA (cDNA) represents the most commonly used gain-of-function approach for interrogating gene functions and for manipulating biological traits. However, this approach is challenging and inefficient for multigene expression due to increased labor for cloning, limited vector capacity, requirement of multiple promoters and terminators, and variable transgene expression levels. Synthetic transcriptional activators provide a promising alternative strategy for gene activation by tethering an autonomous transcription activation domain (TAD) to an intended gene promoter at endogenous genomic locus through a programmable DNA-binding module. Among the known custom DNA-binding modules, the nuclease-dead Streptococcus pyogenes Cas9 (dCas9) protein, which recognizes a specific DNA target through base pairing between a synthetic guide RNA (sgRNA) and DNA, outperforms zinc finger proteins (ZFPs) and transcription activator-like effectors (TALEs), both of which target through protein-DNA interactions1. Recently, three potent dCas9-based transcriptional activation systems, namely VPR, SAM, and Suntag, have been developed for animal cells2–6. However, an efficient dCas9-based transcriptional activation platform is still lacking for plant cells7–9. Here, we developed a new potent dCas9-TAD named dCas9-TV through plant cell-based screens, which confers far stronger transcriptional activation of a single or multiple target genes than the routinely used dCas9-VP64 activator in both plant and mammalian cells.
The prognostic significance of the CD45RO/CD68 ratio was higher than that of the LMR. The CD45RO/CD68 ratio is a useful independent prognostic marker in patients with pT3N0M0 ESCC who have undergone complete resection without neoadjuvant therapy.
The history of immunizing animals with fetal tissues to generate an antitumor response dates back a century ago. Subsequent reports supported the idea that vaccination with embryonic materials could generate cancer-specific immunity and protect animals from transplantable and chemically induced tumors. In our study, we found C57 BL/6 mice vaccinated with embryonic stem cells (ESCs) received obvious antitumor immunity, which protected them from the formation and development of lung cancer. Furthermore, we investigated the antitumor effects of administration of ESCs in mice with minor and/or heavy tumor load. The tumor growth was monitored, the proliferation of lymphocytes and secretion of cytokines were examined, and finally the tissue sections were approached by immunohistochemical and apoptosis staining. The results suggested that mice injected with ESCs received obvious tumor inhibition and retardation due to significant lymphocyte proliferation and cytokine secretion, which help to rebuild the host's immunity against cancer to some extent and comprise the main part of antitumor immunity. Moreover, mice with minor tumor load received stronger antitumor effect compared with mice with heavy tumor load, may be due to relatively intact immune system. Thus, besides their function as prophylactic vaccines, administration of ESCs could be a potential treatment for cancer, which obviously prevent and control the proliferation and development of malignant tumors.
IMPORTANCE Information about stage of cancer at diagnosis, use of therapy, and survival among patients from different racial/ethnic groups with 1 of the most common cancers is lacking. OBJECTIVE To assess stage of cancer at diagnosis, use of therapy, overall survival (OS), and cancerspecific survival (CSS) in patients with cancer from different racial/ethnic groups. DESIGN, SETTING, AND PARTICIPANTS This cohort study included 950 377 Asian, black, white, and Hispanic patients who were diagnosed with prostate, ovarian, breast, stomach, pancreatic, lung, liver, esophageal, or colorectal cancers from January 2004 to December 2010. Data were collected using the Surveillance, Epidemiology, and End Results (SEER) database, and patients were observed for more than 5 years. Data analysis was conducted in July 2018. MAIN OUTCOMES AND MEASURES Multivariable logistic and Cox regression were used to evaluate the differences in stage of cancer at diagnosis, treatment, and survival among patients from different racial/ethnic groups. RESULTS A total of 950 377 patients (499 070 [52.5%] men) were included in the study, with 681 251 white patients (71.7%; mean [SD] age, 65 [12] years), 116 015 black patients (12.2%; mean [SD] age, 62 [12] years), 65 718 Asian patients (6.9%; mean [SD] age, 63 [13] years), and 87 393 Hispanic patients (9.2%; mean [SD] age, 61 [13] years). Compared with Asian patients, black patients were more likely to have metastatic disease at diagnosis (odds ratio [OR], 1.144; 95% CI, 1.109-1.180; P < .001). Black and Hispanic patients were less likely to receive definitive treatment than Asian patients
Extensive-stage small-cell lung cancer patients with metastasis to the liver alone or in combination with other organs appear to have worse outcomes.
Background: Diet and nutrients play an important role in cancer development and progress; a healthy dietary pattern has been found to be associated with several types of cancer. However, the association between a healthy eating pattern and lung cancer risk is still unclear. Objective: Therefore, we conducted a systematic review with meta-analysis to evaluate whether a healthy eating pattern might reduce lung cancer risk. Methods: We identified relevant studies from the PubMed and Embase databases up to October 2015, and the relative risks were extracted and combined by the fixed-effects model when no substantial heterogeneity was observed; otherwise, the random-effects model was employed. Subgroup and publication bias analyses were also performed. Results: Finally, eight observational studies were included in the meta-analysis. The pooled relative risk of lung cancer for the highest vs. lowest category of healthy dietary pattern was 0.81 (95% confidence interval, CI: 0.75–0.86), and no significant heterogeneity was detected. The relative risks (RRs) for non-smokers, former smokers and current smokers were 0.89 (95% CI: 0.63–1.27), 0.74 (95% CI: 0.62–0.89) and 0.86 (95% CI: 0.79–0.93), respectively. The results remained stable in subgroup analyses by other confounders and sensitivity analysis. Conclusions: The results of our meta-analysis suggest that a healthy dietary pattern is associated with a lower lung cancer risk, and they provide more beneficial evidence for changing the diet pattern in the general population.
BackgroundEGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20–30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation.MethodsTraining group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR.ResultsTraining group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (PmiR-21 = 0.004, PmiR-27a = 0.009, PmiR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34).ConclusionsHigher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.
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