Small cell lung cancer (SCLC) represents one of the most aggressive malignancies among cancer types. Not only tumor sample availability is limited, but also the ability for tumor cells to rapidly acquire drug resistance are the rate-limiting bottlenecks for overall survival in current clinical settings. A liquid biopsy capable of capturing and enriching circulating tumor cells (CTCs), together with the possibility of drug screening, is a promising solution. Here, we illustrate the development of a highly efficient ex vivo CTC expansion system based on binary colloidal crystals substrate. Clinical samples were enrolled from 22 patients with SCLC in the study. The CTCs were enriched and expanded from the collected peripheral blood samples. Expanded cells were analyzed for protein expression and observed for drug sensitivity with the use of immunofluorescence and ATP titer evaluation, respectively. Successful CTC spheroid proliferation was established after 4 weeks within 82% of all the collected peripheral blood samples from enrolled patients. Upon immunofluorescence analysis, the enriched cells showed positive markers for EpCAM, TTF-1, synaptophysin and negative for CD45. Additionally, the expanded CTCs demonstrated marked heterogeneity in the expression of E-cadherin and N-cadherin. In a preliminary case series, the drug sensitivity of patient-derived CTC to cisplatin and etoposide was studied to see the correlation with the corresponding therapeutic outcome. In conclusion, our study demonstrates that it is possible to efficiently expand CTCs from SCLC within a clinically relevant time frame; the biomarker information generated from enriched CTCs can assist the selection of effective drugs and improve disease outcome.

Predicting complex disease risks on the basis of individual genomic profiles is an advancing field in human genetics^1,2. However, most genetic studies have focused on populations of European ancestry, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups^3,4. The Taiwan Precision Medicine Initiative recruited more than half a million Taiwanese residents, providing a large dataset of genetic profiles and electronic medical record data for people with Han Chinese ancestry. Using extensive phenotypic data, we conducted comprehensive genomic analyses across the medical phenome with individuals genetically similar to Han Chinese reference populations. These analyses identified population-specific genetic risk variants and new findings for various complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among people of East Asian ancestry in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 10.3% of the overall health variation in the Taiwan Precision Medicine Initiative cohort. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk-prediction models, assessing their performance and identifying the genetic effect on health serves as a model for similar studies in other diverse study populations.

Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment.

Background and Purpose: Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad‐spectrum pharmacological properties including anti‐microbial, anti‐diabetic and anti‐tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti‐angiogenic mechanisms of a novel 2‐aminobenzimidazole‐based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor.Experimental Approach: Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF‐A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti‐angiogenic effects of Jzu 17.Key Results: Jzu 17 inhibited VEGF‐A‐induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF‐A‐induced microvessel sprouting ex vivo and attenuated VEGF‐A‐ or tumour cell‐induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR‐2 and its downstream signalling molecules in VEGF‐A‐stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR‐2 with high affinity.Conclusions and Implications: Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF‐A‐VEGFR‐2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis‐related diseases.