Explore the vast range of titles available.

Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R 2  = 0.87, p  < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies. The detection of aberrations in circulating tumour DNA represents a non-invasive method to survey the oncogenes and tumour suppressors that are modified within a patient’s cancer. Here, the authors analysed more than 10,000 patients using a targeted sequencing panel and report on the frequencies of the mutations that they found.

A novel combined actuation method based on the piezoelectric effect and liquid crystal backflow effect is proposed in this paper. The coupling mechanism of a piezoelectric transducer (PZT) and liquid crystal (LC) in a combined driving mode is analyzed, and the governing equations of electromechanical coupling based on inverse piezoelectric effect and the classical Leslie–Ericksen backflow equation are modified under combined driving method. The new multifield coupling dynamic equations for numerical analysis is established. Experimentally, a sandwiched micropump was manufactured and sealed with wet etching technology on a glass wafer. A testing platform was built to analyze the particles motion and the flow rates were measured with both single PZT or LC actuation and combined actuation. Comparing the results of the numerical analysis and experimental testing of the flow rate and LC molecule motion under different driving voltages and frequencies, the performance of the PZT/LC combined driving is found to be superior to that of the single driving mode (PZT or LC driving) under the same driving conditions. Moreover, the new combined driving mode overcome the disadvantages of single driving mode and enhance the driving efficiency significantly. The simulation results are in good agreement with the experimental data. The maximum flow rate of the micropump achieved was 4.494 μL/min with combined driving method.

Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I–III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity ( p  = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991–61.29, p  < 0.0001 and HR = 7.664, 95% CI, 2.916–21.06, p  = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.

As a promising concept, microfluidic paper-based analytical devices (μPADs) have seen rapid development in recent years. In this study, a new method of fabricating μPADs by atom stamp printing (ASP) is proposed and studied. The advantages of this new method compared to other methods include its low cost, ease of operation, high production efficiency, and high resolution (the minimum widths of the hydrophilic channels and hydrophobic barriers are 328 and 312 μm, respectively). As a proof of concept, μPADs fabricated with the ASP method were used to detect different concentrations of Cu2+ via a colorimetric method. Moreover, combined with a distance-based detection method, these devices achieved a Cu2+ detection limit of down to 1 mg/L. In addition, a new paper-based solid–liquid extraction device (PSED) based on a three-dimensional (3D) μPAD with a “3 + 2” structure and a recyclable extraction mode was developed. Specifically, using the characteristics of paper filtration and capillary force, the device completed multiple extraction and filtration steps from traditional solid–liquid extraction processes with high efficiency. The developed PSED platform allows the detection of heavy metal ions much more cheaply and simply and with a faster response time at the point of care, and it has great promise for applications in food safety and environmental pollution in resource-limited areas.Microfluidics: Putting a stamp on extractionResearchers in China have developed a method of making microfluidic paper-based analytical devices (µPADs) and used it to fabricate a µPAD which detects and extracts heavy metal ions. A team led by Yanfang Guan and Baichuan Sun of Henan University of Technology tested µPAD fabrication via atom stamp printing, in which laser-engraved stamps are used to print hydrophobic channels on paper. The technique produced µPADs with channels around 300 µm wide at a relatively low cost. Next, the team used this approach to create a 3D µPAD which could detect and extract Cu, Zn, Pb. etc. from a solution. The device preformed at least as well as traditional methods but is portable, cheaper, and easier to use. This proof of concept demonstrates the value and utility of such devices in areas such as food safety and pollution management.

Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance. Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy. Intratumoral immunity heterogeneity is poorly characterized. Here the authors apply exome sequencing, transcriptome profiling and T-cell repertoire profiling to multiple loci of non-small-cell lung cancer patients' biopsies and find high spatial immune heterogeneity with local mutational burden correlating with T-cell clonal expansion but not with cytotoxicity.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment. Multi-region sequencing of small cell lung cancers (SCLC) can improve our understanding of the disease. Here the authors analyse 120 multi-region samples from 40 SCLC patients with whole exome sequencing and characterise their mutational burden, evolution, heterogeneity, and potential prognostic biomarkers.

The germline mutation landscape in Chinese lung cancer patients has not been well defined. In this study, sequencing data of 1,021 cancer genes of 1,794 Chinese lung cancer patients was analyzed. A total of 111 pathogenic or likely pathogenic germline mutations were identified, significantly higher than non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline mutations are associated with earlier onset age (median 52.5 vs 60 years-old, p  = 0.008). Among 29 cancer disposition genes with germline mutations detected in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are identified in both cohorts and BRCA2 mutations are significantly more common in Chinese cohort ( p  = 0.015). Chinese patients with germline mutations have different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations compared to those without. Our findings suggest potential ethnic and etiologic differences between Western and Asian lung cancer patients. Germline variants that predispose to lung cancer have been mostly studied in Western populations, but data from Chinese patients is lacking. Here the authors analyze lung cancer germline variants in 1794 Chinese patients, finding exclusive variants or with different frequency compared to TCGA data.

Subclonal architecture and genomic evolution of small-cell lung cancer (SCLC) under treatment has not been well studied primarily due to lack of tumor specimens, particularly longitudinal samples acquired during treatment. SCLC is characterized by early hematogenous spread, which makes circulating cell-free tumor DNA (ctDNA) sequencing a promising modality for genomic profiling. Here, we perform targeted deep sequencing of 430 cancer genes on pre-treatment tumor biopsies, as well as on plasma samples collected prior to and during treatment from 22 SCLC patients. Similar subclonal architecture is observed between pre-treatment ctDNA and paired tumor DNA. Mean variant allele frequency of clonal mutations from pre-treatment ctDNA is associated with progression-free survival and overall survival. Pre- and post-treatment ctDNA mutational analysis demonstrate that mutations of DNA repair and NOTCH signaling pathways are enriched in post-treatment samples. These data suggest that ctDNA sequencing is promising to delineate genomic landscape, subclonal architecture, and genomic evolution of SCLC. Small cell lung cancer (SCLC) may evolve under treatment. But tumor tissues are often not available to study evolution of SCLC. Here, the authors utilize circulating tumor DNA to investigate the genomic evolution and subclonal architecture of SCLC during therapy.

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p  = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p  = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor ( p  = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p  < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p  = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p  = 0.001) and non-EGFR-treated patients (HR 0.308, p  = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.

Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.