Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment ...remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Hypoxia plays a critical role during the evolution of malignant cells and tumour microenvironment (TME).Tumour-derived exosomes contain informative microRNAs involved in the interaction of cancer and ...stromal cells, thus contributing to tissue remodelling of tumour microenvironment. This study aims to clarify how hypoxia affects tumour angiogenesis through exosomes shed from lung cancer cells. Lung cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. miR-23a was significantly upregulated in exosomes from lung cancer under hypoxic conditions. Exosomal miR-23a directly suppressed its target prolyl hydroxylase 1 and 2 (PHD1 and 2), leading to the accumulation of hypoxia-inducible factor-1 α (HIF-1 α) in endothelial cells. Consequently, hypoxic lung cancer cells enhanced angiogenesis by exosomes derived from hypoxic cancer under both normoxic and hypoxic conditions. In addition, exosomal miR-23a also inhibits tight junction protein ZO-1, thereby increasing vascular permeability and cancer transendothelial migration. Inhibition of miR-23a by inhibitor administration decreased angiogenesis and tumour growth in a mouse model. Furthermore, elevated levels of circulating miR-23a are found in the sera of lung cancer patients, and miR-23a levels are positively correlated with proangiogenic activities. Taken together, our study reveals the clinical relevance and prognostic value of cancer-derived exosomal miR-23a under hypoxic conditions, and investigates a unique intercellular communication, mediated by cancer-derived exosomes, which modulates tumour vasculature.
Meta-analyses were conducted to characterize patterns of mutation incidence in non small-cell lung cancer (NSCLC).
Nine genes with the most complete published mutation coincidence data were ...evaluated. One meta-analysis generated a ‘mutMap’ to visually represent mutation coincidence by ethnicity (Western/Asian) and histology (adenocarcinoma ADC or squamous cell carcinoma). Another meta-analysis evaluated incidence of individual mutations. Extended analyses explored incidence of EGFR and KRAS mutations by ethnicity, histology, and smoking status.
Genes evaluated were TP53, EGFR, KRAS, LKB1, EML4-ALK, PTEN, BRAF, PIK3CA, and ErbB2. The mutMap highlighted mutation coincidences occurring in ≥5% of patients, including TP53 with KRAS or EGFR mutations in patients with ADC, and TP53 with LKB1 mutation in Western patients. TP53 was the most frequently mutated gene overall. Frequencies of TP53, EGFR, KRAS, LKB1, PTEN, and BRAF mutations were influenced by histology and/or ethnicity. Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups.
Potential molecular pathology segments of NSCLC were identified. Further studies of mutations in NSCLC are warranted to facilitate more specific diagnoses and guide treatment.
The phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal ...growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC).
Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP G 1250 mg/m(2) i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m(2) i.v. day 1, (3-weekly cycle) for up to four cycles. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety.
A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63-1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP.
These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965).
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) ...was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines.
By combining angle-resolved photoemission spectroscopy and quantum oscillation measurements, we performed a comprehensive investigation on the electronic structure of LaSb, which exhibits ...near-quadratic extremely large magnetoresistance (XMR) without any sign of saturation at magnetic fields as high as 40 T. We clearly resolve one spherical and one intersecting-ellipsoidal hole Fermi surfaces (FSs) at the Brillouin zone (BZ) center Γ and one ellipsoidal electron FS at the BZ boundary X. The hole and electron carriers calculated from the enclosed FS volumes are perfectly compensated, and the carrier compensation is unaffected by temperature. We further reveal that LaSb is topologically trivial but shares many similarities with the Weyl semimetal TaAs family in the bulk electronic structure. Based on these results, we have examined the mechanisms that have been proposed so far to explain the near-quadratic XMR in semimetals.
Background
Childhood asthma comprises different phenotypes with complex pathophysiology. Different asthma phenotypes evoke various clinical symptoms and vary in their responses to treatments.
Methods
...We applied k‐means clustering algorithm of twelve objective laboratory tests among 351 asthmatic children enrolled in the Taiwanese Consortium of Childhood Asthma Study (TCCAS). We constructed gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with different asthma phenotypes.
Results
Five distinct phenotypes of childhood asthma were identified and can be characterized by either eosinophil‐predominant or neutrophil‐predominant inflammatory characteristics. In the gene expression profile analysis, significant differences were noted for neutrophil‐predominant asthma, compared with samples from all the other asthma phenotypes. The vast majority of the differentially expressed genes in neutrophil‐predominant asthma was associated with corticosteroid response. From an independent inhaled corticosteroid (ICS) response cohort, we also found neutrophils could be activated in this severe asthma phenotype and neutrophil‐predominant asthma may be associated with corticosteroid nonresponsiveness.
Conclusion
Phenotype clustering of childhood asthma can be helpful to identify clinically relevant patients and reveal different inflammatory characteristics in asthmatic children. Neutrophil‐predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Gene expression profile of different asthma phenotypes not only improve our knowledge of childhood asthma, but also can guide asthma precision medicine.
Neutrophil‐predominant asthma is the most severe asthma phenotype with poor corticosteroid response. Five distinct phenotypes of childhood asthma identified in this study with differences in lung function, symptom frequency, healthcare utilization, percentages of eosinophils and neutrophils in peripheral blood, and serum IgE. Gene expression signature in PBMC constitutes an easier way to objectively identify corticosteroid‐resistant asthma in clinical settings.
This phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM).
Forty-eight patients ...aged 18–75 years with Eastern Cooperative Oncology Group performance status 0–2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST.
The median PFS was 10.1 months 95% confidence interval (CI) 7.1–12.3 for intracranial progression and 9.7 months (95% CI 2.5–17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease 15.2 months (95% CI 8.3–22.2) versus 4.4 months (95% CI 0.0–11.6); P = 0.02. The median overall survival was 18.9 months (95% CI 14.4–23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2.
Single-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.
To understand the status of oropharyngeal yeast colonization in human immunodeficiency virus (HIV) -infected outpatients in the era of highly active antiretroviral therapy (HAART), we conducted a ...prospective, cross-sectional study from October 2009 to January 2010 at a medical centre in southern Taiwan. Fungal cultures of the oropharyngeal swabs were performed on 327 enrolled patients. At enrolment, 258 (79%) patients had been receiving HAART, and 42 (12.8%), 73 (22.3%) and 212 (64.8%) patients had CD4 cell counts ≤200, 201–350, and >350 cells/mm3, respectively. Oral yeast colonization was detected in 193 (59%) patients, among whom 157 (81.3%), 25 (13.0%), and 11 (5.7%) were colonized by a single, two and more than two species, respectively. Multivariate analysis showed that receipt of efavirenz-containing regiments and CD4 cell counts >200 cells/mm3 were associated with lower risks of oral yeast colonization, while intravenous drug users were at a higher risk. Among the 241 isolates recovered, Candida albicans accounted for 69.7%, followed by C. dubliniensis (9.5%), C. glabrata (8.3%), C. tropicalis (3.3%), C. intermedia (2.1%), C. parapsilosis (1.7%), and 11 other species (5.4%). Overall, 230 (95.4%), 236 (97.9%) and 240 (99.6%) isolates were susceptible to fluconazole, voriconazole and amphotericin B, respectively. In conclusion, colonization by C. dubliniensis has emerged in recent years. In addition to a CD4 cell count ≤200 cells/mm3, which is a known risk factor for oropharyngeal yeast colonization in HIV-infected patients that was identified in our previous studies, two risk factors, non-receipt of efavirenz-based combinations and intravenous drug use, were first identified in the present study. Fluconazole remained effective in vitro against the yeasts colonizing the oropharynx in this population.
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