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.
Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) ...metastasis and chemoresistance have not been fully characterized.
CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
Background
IL‐25 has been proposed to play a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the association of IL‐25 with the ...Th2‐biased inflammatory profiles in CRSwNP.
Methods
Nasal polyp (NP) tissues and control uncinate process tissues were collected from 92 patients with CRSwNP, 20 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 16 normal control subjects. IL‐25 expression was examined using immunohistochemistry and immunofluorescence staining, flow cytometry, RT‐qPCR, and ELISA. The inflammatory profiles and clinical characteristics of 2 NP subtypes (IL‐25high and IL‐25low) were evaluated, and the effects of IL‐25 on Th2 cytokine production in cultured dispersed polyp cells were examined in vitro.
Results
The mRNA and protein levels of IL‐25 were significantly increased in the polyp tissues compared with the control uncinate process tissues. The IL‐25high subtype showed greater computed tomography scores, endoscopic scores, and Th2 response. Exposure to IL‐25 activated type 2 innate lymphoid cells and Th2 cells in NP simultaneously which further increased Th2 cytokine production in vitro.
Conclusions
Local IL‐25 plays a crucial role in promoting Th2‐biased inflammatory profiles in NP and may serve as a promising therapeutic target in CRSwNP patients.
High-β_{θe} (a ratio of the electron thermal pressure to the poloidal magnetic pressure) steady-state long-pulse plasmas with steep central electron temperature gradient are achieved in the ...Experimental Advanced Superconducting Tokamak. An intrinsic current is observed to be modulated by turbulence driven by the electron temperature gradient. This turbulent current is generated in the countercurrent direction and can reach a maximum ratio of 25% of the bootstrap current. Gyrokinetic simulations and experimental observations indicate that the turbulence is the electron temperature gradient mode (ETG). The dominant mechanism for the turbulent current generation is due to the divergence of ETG-driven residual flux of current. Good agreement has been found between experiments and theory for the critical value of the electron temperature gradient triggering ETG and for the level of the turbulent current. The maximum values of turbulent current and electron temperature gradient lead to the destabilization of an m/n=1/1 kink mode, which by counteraction reduces the turbulence level (m and n are the poloidal and toroidal mode number, respectively). These observations suggest that the self-regulation system including turbulence, turbulent current, and kink mode is a contributing mechanism for sustaining the steady-state long-pulse high-β_{θe} regime.
Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial.
In total, 2031 ...consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian-specific BMI (kg m(-2)) cutoff values. The impact of BMI on overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models. We performed a meta-analysis to examine the association of BMI with OS and postoperative complication.
Patients with higher BMI had more postoperative complication (P=0.002), such as anastomotic leakage (P=0.016) and cardiovascular diseases (P<0.001), but less incidence of chylous leakage (P=0.010). Logistic regression analysis showed that BMI (P=0.005) was a confounding factor associated with postoperative complication. Multivariate analysis showed that overweight and obese patients had a more favourable survival than normal weight patients (HR (hazard ratio) = 0.80, 95% CI (confidence interval): 0.70-0.92, P=0.001). Subgroup analysis showed that the association with higher BMI and increased OS was observed in patients with oesophageal squamous cell carcinoma (ESCC) (P<0.001), oesophageal adenocarcinoma (EA) (P=0.034), never-smoking (P=0.035), ever-smoking (P=0.035), never alcohol consumption (P=0.005), weight loss (P=0.003) and advanced pathological stage (P<0.001). The meta-analysis further corroborated that higher BMI was associated with increased complication of anastomotic leakage (RR (risk ratio)=1.04, 95% CI: 1.02-1.06, P=0.001), wound infection (RR=1.03, 95% CI: 1.00-1.05, P=0.031) and cardiovascular diseases (RR=1.02, 95% CI: 1.00-1.05, P=0.039), but decreased incidence of chylous leakage (RR=0.98, 95% CI: 0.96-0.99, P<0.001). In addition, high BMI could significantly improved OS (HR=0.78, 95% CI: 0.71-0.85, P<0.001).
Preoperative BMI was an independent prognostic factor for survival, and strongly associated with postoperative complications in oesophageal cancer.
Black carbon (BC) aerosol at high altitudes of the Qinghai–Tibetan Plateau has potential effects on the regional climate and hydrological cycle. An intensive measurement campaign was conducted at ...Qinghai Lake (~ 3200 m above sea level) at the edge of the northeastern Qinghai–Tibetan Plateau during winter using a ground-based single particle soot photometer (SP2) and a photoacoustic extinctiometer (PAX). The average concentration of refractory BC (rBC) and number fraction of coated rBC were found to be 160 ± 190 ng m−3 and 59 % for the entire campaign, respectively. Significant enhancements of rBC loadings and number fraction of coated rBC were observed during a pollution episode, with an average value of 390 ng m−3 and 65 %, respectively. The mass size distribution of rBC particles showed log-normal distribution, with a peak diameter of ~ 187 nm regardless of the pollution level. Five-day backward trajectory analysis suggests that the air masses from north India contributed to the increased rBC loadings during the campaign. The potential source contribution function (PSCF) model combined with the fire counts map further proves that biomass burning from north India is an important potential source influencing the northeastern Qinghai–Tibetan Plateau during the pollution episode. The rBC mass absorption cross section (MACrBC) at λ = 532 nm was slightly larger in clean days (14.9 m2 g−1) than during the pollution episode (9.3 m2 g−1), likely due to the effects of brown carbon and the uncertainty of the MACrBC calculation. The MACrBC was positively correlated with number fraction of coated rBC during the pollution episode with an increasing rate of 0.18 (m2 g−1) %−1. The number fraction of coated rBC particles showed positive correlation with light absorption, suggesting that the increase of coated rBC particles will enhance the light absorption. Compared to rBC mass concentration, rBC mixing sate is more important in determining absorption during the pollution episode, estimated from the same percentage-wise increment of either rBC mass concentration or the number fraction of coated rBC. The estimated BC direct radiative forcing was +0.93 W m−2 for the pollution episode, which is 2 times larger than that in clean days. Our study provides insight into the potential climatic impacts of rBC aerosol transported to the Qinghai–Tibetan Plateau from south Asian regions, and is also useful for future modeling studies.
An overview of Sun–Sky Radiometer Observation Network (SONET) measurements in China is presented. Based on observations at 16 distributed SONET sites in China, atmospheric aerosol parameters are ...acquired via standardization processes of operational measurement, maintenance, calibration, inversion, and quality control implemented since 2010. A climatology study is performed focusing on total columnar atmospheric aerosol characteristics, including optical (aerosol optical depth, ÅngstrÖm exponent, fine-mode fraction, single-scattering albedo), physical (volume particle size distribution), chemical composition (black carbon; brown carbon; fine-mode scattering component, coarse-mode component; and aerosol water), and radiative properties (aerosol radiative forcing and efficiency). Data analyses show that aerosol optical depth is low in the west but high in the east of China. Aerosol composition also shows significant spatial and temporal variations, leading to noticeable diversities in optical and physical property patterns. In west and north China, aerosols are generally affected by dust particles, while monsoon climate and human activities impose remarkable influences on aerosols in east and south China. Aerosols in China exhibit strong light-scattering capability and result in significant radiative cooling effects.
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