ObjectiveTo assess the association between PD-L1 expression and driver gene mutations in patients with non-small-cell lung cancer (NSCLC).MethodWe performed a meta-analysis of 26 studies (7541 patients) which were published from 2015 to 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated to describe the correlation. Subgroup analysis was performed based on population characteristics, types of PD-L1 antibodies and quality of individual studies.ResultsA lower frequency of PD-L1 positivity was observed in NSCLCs harboring EGFR mutation (OR: 0.64, 95% CI, 0.45–0.91, p = 0.014). A negative correlation was also found at 1% (OR: 0.35, 95% CI, 0.22–0.55, p = 0.000) and 50% (OR: 0.33, 95% CI, 0.14–0.81, p = 0.015) cutoff for PD-L1 positive, elderly age group (OR: 0.56, 95% CI, 0.35–0.89, p = 0.013), female dominant group (OR: 0.55, 95% CI, 0.29–0.94, p = 0.030) and smoker dominant group (OR: 0.52, 95% CI, 0.29–0.96, p = 0.035). No significant differences in PD-L1 expression were observed among patients with different ALK, BRAF, HER2, PIK3CA status and MET expression level. Higher level of PD-L1 was found in tumors with KRAS mutation (OR: 1.45, 95% CI, 1.18–1.80, p = 0.001). PD-L1 expression level was not significantly different between triple (EGFR/ALK/KRAS) wild type NSCLCs and those with EGFR/ALK/KRAS mutation.ConclusionsPD-L1 expression in EGFR mutated NSCLCs were lower than those in EGFR wild type NSCLCs, while tumors with KRAS mutation showed higher levels of PD-L1.

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Immune checkpoint inhibitors (ICIs) have brought impressive clinical benefits in a variety of malignancies over the past years, which dramatically revolutionized the cancer treatment paradigm. Monotherapy or in combination with chemotherapy of ICIs targeting programmed death 1/programmed death ligand 1 (PD-L1) has emerged as an alternative treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, constrained by primary or acquired resistance, most patients obtain limited benefits from ICIs and occasionally suffer from severe immune-related adverse events. Moreover, owing to the complexity of the tumor microenvironment and the technical limitations, clinical application of PD-L1 and tumor mutation burden as biomarkers shows many deficiencies. Thus, additional predictive biomarkers are required to further advance the precision of proper patient selection, avoiding the exposure of potential nonresponders to unnecessary immunotoxicity. Nowadays, an increasing number of investigations are focusing on peripheral blood as a noninvasive alternative to tissue biopsy in predicting and monitoring treatment outcomes. Herein, we summarize the emerging blood-based biomarkers that could predict the clinical response to checkpoint immunotherapy, specifically in patients with NSCLC.

In vitro 3D hepatocyte culture constitutes a core aspect of liver tissue engineering. However, conventional 3D cultures are unable to maintain hepatocyte polarity, functional phenotype, or viability. Here, we employed microfluidic chip technology combined with natural alginate hydrogels to construct 3D liver tissues mimicking hepatic plates. We comprehensively evaluated cultured hepatocyte viability, function, and polarity. Transcriptome sequencing was used to analyze changes in hepatocyte polarity pathways. The data indicate that, as culture duration increases, the viability, function, polarity, mRNA expression, and ultrastructure of the hepatic plate mimetic 3D hepatocytes are enhanced. Furthermore, hepatic plate mimetic 3D cultures can promote changes in the bile secretion pathway via effector mechanisms associated with nuclear receptors, bile uptake, and efflux transporters. This study provides a scientific basis and strong evidence for the physiological structures of bionic livers prepared using 3D cultures. The systems and cultured liver tissues described here may serve as a better in vitro 3D culture platform and basic unit for varied applications, including drug development, hepatocyte polarity research, bioartificial liver bioreactor design, and tissue and organ construction for liver tissue engineering or cholestatic liver injury.

A general mathematical model for performance evaluation of acetone-butanol continuous flash extractive fermentation system was formulated in the terms of productivity, energy requirement (energy utilization efficiency) and product purity. The simulation results based on experimental data showed that the most pronounced performance improvement could be achieved by using highly concentrated substrate as feed and the increase in solvent dilution rate could only improve the total productivity at the expense of energy utilization efficiency. A two-vessel partial flash system, with the first vessel of two to three plates and the second vessel as a complete flash vessel, is required to ensure high product purity. This method of mathematical formulation and analysis could be used and extended as a general tool to other bioprocesses equipped with multiple in situ recovery systems.