Abstract Epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) translocations in non-small cell lung cancer (NSCLC) are mutually exclusive. However, several ...exceptional cases harboring both genetic alterations have been reported. In this study, a total of 444 patients with lung adenocarcinoma were examined for their EGFR and ALK status at Seoul National University Hospital between July 2008 and September 2011. EGFR mutations and ALK translocations were detected in 228 (51.4%) and 34 (7.7%) patients, respectively. Four patients (0.9%) had both genetic alterations and three underwent curative surgery. One patient who received both EGFR tyrosine kinase and ALK inhibitors, separately showed an objective response to the ALK inhibitor alone. Considering our and previous studies, patients harboring both EGFR mutation and ALK translocation showed differential sensitivities to both targeted therapies, suggesting a variable dependence on EGFR and ALK oncogenes.
Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large ...amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.
The mutualistic relationship between alien plant species and microorganisms is proposed to facilitate or hinder invasive success, depending on whether plants can form novel associations with ...microorganisms in the introduced habitats. However, this hypothesis has not considered seed endophytes that would move together with plant propagules. Little information is available on the seed endophytic bacteria of invasive species and their effects on plant performance. We isolated the seed endophytic bacteria of a xerophytic invasive plant, Lactuca serriola, and examined their plant growth-promoting traits. In addition, we assessed whether these seed endophytes contributed to plant drought tolerance. Forty-two bacterial species were isolated from seeds, and all of them exhibited at least one plant growth-promoting trait. Kosakonia cowanii occurred in all four tested plant populations and produced a high concentration of exopolysaccharides in media with a highly negative water potential. Notably, applying K. cowanii GG1 to Arabidopsis thaliana stimulated plant growth under drought conditions. It also reduced soil water loss under drought conditions, suggesting bacterial production of exopolysaccharides might contribute to the maintenance of soil water content. These results imply that invasive plants can disperse along with beneficial bacterial symbionts, which potentially improve plant fitness and help to establish alien plant species.
Genomic and precision medicine research has afforded notable advances in human cancer treatment, yet applicability to other species remains uncertain. Through whole-exome and transcriptome analyses ...of 191 spontaneous canine mammary tumors (CMTs) that exhibit the archetypal features of human breast cancers, we found a striking resemblance of genomic characteristics including frequent PIK3CA mutations (43.1%), aberrations of the PI3K-Akt pathway (61.7%), and key genes involved in cancer initiation and progression. We also identified three gene expression-based CMT subtypes, one of which segregated with basal-like human breast cancer subtypes with activated epithelial-to-mesenchymal transition, low claudin expression, and unfavorable disease prognosis. A relative lack of ERBB2 amplification and Her2-enrichment subtype in CMT denoted species-specific molecular mechanisms. Taken together, our results elucidate cross-species oncogenic signatures for a better understanding of universal and context-dependent mechanisms in breast cancer development and provide a basis for precision diagnostics and therapeutics for domestic dogs.
Chameleons use a non-close-packed array of guanine nanocrystals in iridophores to develop and tune skin colors in the full visible range. Inspired by the biological process uncovered in panther ...chameleons, we designed photonic films containing a non-close-packed face-centered-cubic array of silica particles embedded in an elastomer. The non-close-packed array is formed by interparticle repulsion exerted by solvation layers on the particle surface, which is rapidly captured in the elastomer by photocuring of the dispersion medium. The artificial skin exhibits a structural color that shifts from red to blue under stretching or compression. The separation between inelastic particles enables tuning without experiencing significant rearrangement of particles, providing elastic deformation and reversible color change, as chameleons do. The simple fabrication procedure consists of film casting and UV irradiation, potentially enabling the continuous high-throughput production. The mechanochromic property of the photonic films enables the visualization of deformation or stress with colors, which is potentially beneficial for various applications, including mechanical sensors, sound–vision transformers, and color display.
Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) serve as a unique source for cell therapy. We investigated whether exosomes from iMSCs promote the proliferation of human ...keratinocytes (HaCaT) and human dermal fibroblasts (HDFs). iPSCs were established from human Wharton's jelly MSCs and were allowed to differentiate into iMSCs. Exosomes were collected from the culture supernatant of MSCs (MSC-exo) and iMSCs (iMSC-exo), and their characteristics were investigated. Both exosome types possessed basic characteristics of exosomes and were taken up by skin cells in vitro and in vivo. A significant increase in HaCaT proliferation was observed with iMSC-exo, although both exosomes increased the viability and cell cycle progression in HaCaT and HDFs. No significant difference was observed in the closure of wound scratch and the expression of reparative genes between cells treated with the two exosome types. Both exosomes enhanced the secretion of collagen in HaCaT and HDFs; however, an increase in fibronectin level was observed only in HaCaT, and this effect was better with iMSC-exo treatment. Only iMSC-exo increased the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2. Our results indicate that iMSC-exo promote the proliferation of skin cells by stimulating ERK1/2 and highlight the application of iMSCs for producing exosomes.
Fabry disease is an X-linked lysosomal storage disease caused by a mutation in the galactosidase alpha (GLA) gene. Despite advances in therapeutic technologies, the lack of humanized experimental ...models of Fabry disease has limited the development of new therapies to cure the disease. Herein, we modeled Fabry disease using human inducible pluripotent stem cell (iPSC)-derived kidney organoids and the CRISPR-Cas9 genome-editing system. GLA-mutant human kidney organoids revealed deformed podocytes and tubular cells with accumulation of globotriaosylceramide (Gb3). Ultrastructural analysis showed abundant electron-dense granular deposits and electron-dense lamellate lipid-like deposits that formed concentric bodies (zebra bodies) in the cytoplasm of podocytes and tubules. The oxidative stress level was increased in GLA-mutant kidney organoids, and the increase was accompanied by apoptosis. Enzyme replacement treatment (ERT) with recombinant human α-Gal A decreased the Gb3 accumulation and oxidative stress, which resulted in amelioration of the deformed cellular structure of the GLA-mutant kidney organoids. Transcription profile analyses showed decreased glutathione (GSH) metabolism in GLA-mutant kidney organoids. GSH replacement treatment decreased oxidative stress and attenuated the structural deformity of the GLA-mutant kidney organoids. GSH treatment also increased the expression of podocyte and tubular markers and decreased apoptosis. In conclusion, GLA-mutant kidney organoids derived from human iPSCs are valuable tools for studying the mechanisms and developing novel therapeutic alternatives for Fabry disease.
Tumor metastasis remains the cause of 90% of cancer‐related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple‐negative breast cancers ...(TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)‐like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase‐3/‐7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem‐like traits, concomitant with a reduction in the CD24low/CD44high, CD24high/CD49fhigh subpopulation, ALDH1 activity and mammosphere formation. The BCSC‐enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP‐2 and MMP‐9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC‐like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.
What's new?
Triple‐negative breast cancers (TNBCs) with high levels of cancer stem‐like properties have aggressive metastatic phenotypes and are difficult to treat. Despite chemotherapy, many patients with TNBC die within five years of diagnosis. Here, the authors show that breast cancer cell populations enriched with cancer stem cells (CSCs) exhibit enhanced metastasis and increased STAT3 activation and that STAT3 activation can be inhibited in vitro following administration of the anthelmintic drug flubendazole. In mice with CSC‐enriched TNBC tumors, flubendazole inhibited tumor growth, angiogenesis and lung and liver metastasis. The data warrant additional study of the potential clinical value of flubendazole in TNBC.
Optimal antiplatelet monotherapy during the chronic maintenance period in patients who undergo coronary stenting is unknown. We aimed to compare head to head the efficacy and safety of aspirin and ...clopidogrel monotherapy in this population.
We did an investigator-initiated, prospective, randomised, open-label, multicentre trial at 37 study sites in South Korea. We enrolled patients aged at least 20 years who maintained dual antiplatelet therapy without clinical events for 6–18 months after percutaneous coronary intervention with drug-eluting stents (DES). We excluded patients with any ischaemic and major bleeding complications. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02044250.
Between March 26, 2014, and May 29, 2018, we enrolled 5530 patients. 5438 (98·3%) patients were randomly assigned to either the clopidogrel group (2710 49·8%) or to the aspirin group (2728 50·2%). Ascertainment of the primary endpoint was completed in 5338 (98·2%) patients. During 24-month follow-up, the primary outcome occurred in 152 (5·7%) patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 95% CI 0·59–0·90; p=0·0035).
Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention, clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events.
ChongKunDang, SamJin, HanMi, DaeWoong, and the South Korea Ministry of Health and Welfare.
Circulating soluble programmed death-1 ligand (sPD-L1) is measurable in the serum of cancer patients. This study aimed to investigate the significance of sPD-L1 in cancer patients receiving immune ...checkpoint inhibitor therapy. Blood samples were obtained before and after immune checkpoint inhibitor therapy (January 2015 to January 2019). The study cohort consisted of 128 patients who were diagnosed with non-small cell lung cancer (n = 50), melanoma (n = 31), small cell lung cancer (n = 14), urothelial carcinoma (n = 13), and other cancers (n = 20). Patients with a high level (> 11.0 pg/μL) of sPD-L1 were more likely to exhibit progressive disease compared with those with a low level (41.8% versus 20.7%, p = 0.013). High sPD-L1 was also associated with worse prognosis; the median PFS was 2.9 (95% confidence interval CI 2.1-3.7) months versus 6.3 (95% CI 3.0-9.6) months (p = 0.023), and the median OS was 7.4 (95% CI 6.3-8.5) months versus 13.3 (95% CI 9.2-17.4) months (p = 0.005). In the multivariate analyses, high sPD-L1 was an independent prognostic factor for both decreased PFS (HR 1.928, p = 0.038) and OS (HR 1.788, p = 0.004). sPD-L1 levels did not correlate with tissue PD-L1 expression. However, sPD-L1 levels were positively correlated with neutrophil to lymphocyte ratios and negatively correlated with both the proportion and the total number of lymphocytes. We found that high pretreatment sPD-L1 levels were associated with progressive disease and were an independent prognostic factor predicting lower PFS and OS in these patients.
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