Background
Programmed death‐ligand 1 (PD‐L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase ...inhibitors (TKIs). However, whether PD‐L1 expression plays a role in anaplastic lymphoma kinase (ALK)‐positive lung ADC is unknown. We aimed to evaluate the impact of PD‐L1 in patients with ALK‐positive lung ADC receiving crizotinib.
Materials and Methods
PD‐L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase‐polymerase chain reaction was used for ALK variant detection, and immunofluorescence‐based multiplex staining was applied for exploring immune cells in tumor microenvironments.
Results
A total of 78 patients with ALK‐positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild‐type tumors, PD‐L1 expression was lower in ALK‐positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD‐L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression‐free survival (PFS) was better in tumors with negative PD‐L1 expression (ORR/PFS in PD‐L1 0% vs. 1%–49% vs. 50%–100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD‐L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160–0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD‐L1 expression.
Conclusion
Positive PD‐L1 expression was associated with unfavorable clinical outcomes in patients with ALK‐positive lung ADC receiving crizotinib.
Implications for Practice
Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small‐molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death‐ligand 1 (PD‐L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD‐L1 expression was also associated with worse response rate and shorter progression‐free survival of anaplastic lymphoma kinase (ALK)‐positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD‐L1 compared with long variants (V1, V2, and V6). Testing PD‐L1 before initiating crizotinib for ALK‐positive lung cancer could be a simple method to provide important prognostic information.
This article focuses on the effect of PD‐L1 on ALK‐positive lung adenocarcinoma and examines the association of pretreatment tumor PD‐L1 and clinical outcomes of patients receiving the first approved ALK inhibitor, crizotinib.
Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma ...(ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression.
Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments.
A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1–49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250–0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1–49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses.
Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.
•Pre-treatment PD-L1 can predict TKI response in EGFR mutant lung adenocarcinoma (ADC).•Pre-treatment PD-L1 can predict acquired T790M in EGFR mutant lung ADC after TKI therapy.•PD-L1 negatively correlated with B cells, macrophages, and regulatory T cells in EGFR mutant ADC.•Abundant tumour-infiltrating B cell is associated with good TKI response in EGFR mutant ADC.•Pre-treatment PD-L1 may help select the most appropriate regimen for EGFR mutant ADC.
Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial ...DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca2+, or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.
Background & Aims
Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long‐term entecavir therapy in ...reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB‐related cirrhosis patients.
Methods
The C‐TEAM (Cirrhosis‐Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective–prospective cohort study in Taiwan. We enrolled treatment‐naïve patients with CHB‐related cirrhosis and baseline HBV‐DNA≥2000 IU/mL receiving long‐term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort.
Results
In total, 1315 entecavir‐treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow‐up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28‐0.57. Additionally, an older age, the male gender, HBeAg positivity, alpha‐fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver‐related and all‐cause mortality. These findings were confirmed by propensity score‐matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1‐year virological response were predictive of HCC development.
Conclusions
Four‐year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB‐related cirrhosis.
See Editorial on Page 1752
This work demonstrated the first synthetic application of direct C−H olefinations in the step‐saving preparation of various hole‐transporting materials (HTM) for efficient perovskite solar cells ...(PSC). Cross‐dehydrogenative couplings of naphthodithiophene (NDT) with vinyl arenes under palladium‐catalysis facilely generated various new oligo(hetero)aryls with internal alkenes. Reaction conditions were optimized, which gave the product isolated yields of up to 71 % with high (E)‐stereoselectivity. These readily accessible NDT core‐based small molecules involving olefin as π‐spacers displayed immediate power conversion efficiencies of up to 17.2 % without a device oxidation process that is required for the commercially available spiro‐OMeTAD and most other existing HTMs while fabricated in corresponding PSC devices.
For the first time, C−H/C−H cross‐dehydrogenative couplings (direct C−H olefinations) are used as key step to access small‐molecule hole‐transporting materials (HTMs). NDT core‐based HTMs incorporating additional olefins as π‐spacers substantially improve the PCE of perovskite solar cells of up to 17.2 %.
YES‐associated protein (YAP) is a part of the Hippo pathway, with pivotal roles in several developmental processes and dual functionality as both a tumor suppressor and an oncogene. In the present ...study, we identified YAP activity as a microtubular scaffold protein that maintains the stability of the mitotic spindle and midbody by physically interacting with α‐tubulin during mitotic progression. The interaction of YAP and α‐tubulin was evident in co‐immunoprecipitation assays, as well as observing their co‐localization in the microtubular structure of the mitotic spindle and midbody in immunostainings. With YAP depletion, levels of ECT2, MKLP‐1, and Aurora B are reduced, which is consistent with YAP functioning in midbody formation during cytokinesis. The concomitant decrease in α‐tubulin and increase in acetyl‐α‐tubulin during YAP depletion occurred at the post‐transcriptional level. This suggests that YAP maintains the stability of the mitotic spindle and midbody, which ensures appropriate chromosome segregation during mitotic division. The increase in acetyl‐α‐tubulin during YAP depletion may provide a lesion‐halting mechanism in maintaining the microtubule structure. The depletion of YAP also results in multinuclearity and aneuploidy, which supports its role in stabilizing the mitotic spindle and midbody.
YES‐associated protein (YAP) physically interacts with α‐tubulin in the mitotic spindle and midbody. The post‐translational acetyl‐α‐tubulin increases in YAP depletion. Also, the incidence of multinuclearity and aneuploidy is increased in YAP depletion. Acetyl‐α‐tubulin increment poses a potential lesion‐halting mechanism counteracting mechanical stresses in the mitotic apparatus during YAP depletion. Thus, YAP safeguards the integrity of the microtubular structure in the mitotic spindle and midbody.
The aryl hydrocarbon receptor (AhR) regulates peripheral immunity; but its role in microglia‐mediated neuroinflammation in the brain remains unknown. Here, we demonstrate that AhR mediates both ...anti‐inflammatory and proinflammatory effects in lipopolysaccharide (LPS)‐activated microglia. Activation of AhR by its ligands, formylindolo3,2‐bcarbazole (FICZ) or 3‐methylcholanthrene (3MC), attenuated LPS‐induced microglial immune responses. AhR also showed proinflammatory effects, as evidenced by the findings that genetic silence of AhR ameliorated the LPS‐induced microglial immune responses and LPS‐activated microglia‐mediated neurotoxicity. Similarly, LPS‐induced expressions of tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) were reduced in the cerebral cortex of AhR‐deficient mice. Intriguingly, LPS upregulated and activated AhR in the absence of AhR ligands via the MEK1/2 signaling pathway, which effects were associated with a transient inhibition of cytochrome P450 1A1 (CYP1A1). Although AhR ligands synergistically enhance LPS‐induced AhR activation, leading to suppression of LPS‐induced microglial immune responses, they cannot do so on their own in microglia. Chromatin immunoprecipitation results further revealed that LPS‐FICZ co‐treatment, but not LPS alone, not only resulted in co‐recruitment of both AhR and NFκB onto the κB site of TNFα gene promoter but also reduced LPS‐induced AhR binding to the DRE site of iNOS gene promoter. Together, we provide evidence showing that microglial AhR, which can be activated by LPS, exerts bi‐directional effects on the regulation of LPS‐induced neuroinflammation, depending on the availability of external AhR ligands. These findings confer further insights into the potential link between environmental factors and the inflammatory brain disorders. GLIA 2015;63:1138–1154
Main Points
LPS upregulates and activates AhR in microglia.
AhR mediates the LPS‐induced pro‐inflammatory responses in microglia and mouse brain.
AhR ligand application shunts LPS‐activated AhR to the anti‐inflammatory mode involving AhR‐NFκB crosstalk.
Orchidaceae are well known for their fascinating floral morphologic features, specialized pollination, and distinctive ecological strategies. With their long-lasting flowers of various colors and ...pigmentation patterning, Phalaenopsis spp. have become important ornamental plants worldwide. In this study, we identified three R2R3-MYB transcription factors PeMYB2, PeMYB11, and PeMYB12. Their expression profiles were concomitant with red color formation in Phalaenopsis spp. flowers. Transient assay of overexpression of three PeMYBs verified that PeMYB2 resulted in anthocyanin accumulation, and these PeMYBs could activate the expression of three downstream structural genes Phalaenopsis spp. Flavanone 3-hydroxylase5, Phalaenopsis spp. Dihydroflavonol 4-reductase1, and Phalaenopsis spp. Anthocyanidin synthase3. In addition, these three PeMYBs participated in the distinct pigmentation patterning in a single flower, which was revealed by virus-induced gene silencing. In the sepals/petals, silencing of PeMYB2, PeMYB11, and PeMYB12 resulted in the loss of the full-red pigmentation, red spots, and venation patterns, respectively. Moreover, different pigmentation patterning was regulated by PeMYBs in the sepals/petals and lip. PeMYB11 was responsive to the red spots in the callus of the lip, and PeMYB12 participated in the full pigmentation in the central lobe of the lip. The differential pigmentation patterning was validated by RNA in situ hybridization. Additional assessment was performed in six Phalaenopsis spp. cultivars with different color patterns. The combined expression of these three PeMYBs in different ratios leads to a wealth of complicated floral pigmentation patterning in Phalaenopsis spp.
The purpose of this article is to discuss how to improve the ways the Taiwanese Ground Forces use the common operational picture (COP) for training to improve the efficacy of tactical training and ...understanding of the combat field. Augmented Reality (AR) has made huge progress in the past decade and is widely applied in education, industrial sector, medical industry, military industry. More attention is focused on training simulations for soldiers and improving battlefield perception systems. The application of AR in tactical training is still an emerging realm of research but has a huge potential. Related studies have shown the application and technical limitations of AR technology in the military field. Then, using a user-oriented research method, a tactical training system based on 3D augmented reality is proposed and constructs a system prototype to combine virtual information with the real environment and provide the advantages of intuition, interaction, and information visualization. The experiment had an experimental group and control group, and an independent sample "t" was tested for evaluation and comparison. The experimental results show that the understanding of battlefield situations and tactical actions in the AR-based tactical teaching system has changed significantly. The system prototype and experimental content provide useful contributions to the tactical teaching of the Army Academy, and it can be used as a reference for the development of AR in future military applications.
Chronic kidney disease (CKD)‐associated mental disorders have been attributed to the excessive accumulation of hemodialysis‐resistant indoxyl‐3‐sulfate (I3S) in the brain. I3S not only induces ...oxidative stress but is also a potent endogenous agonist of the aryl hydrocarbon receptor (AhR). Here, we investigated the role of AhR in CKD‐induced brain disorders using a 5/6 nephrectomy‐induced CKD mouse model, which showed increased I3S concentration in both blood and brain, anxiety and impaired novelty recognition, and AhR activation in the anterior cortex. GFAP+ reactive astrocytes were increased accompanied with the reduction of glutamate transporter 1 (GLT1) on perineuronal astrocytic processes (PAPs) in the anterior cingulate cortex (ACC) in CKD mice, and these alterations were attenuated in both neural lineage‐specific and astrocyte‐specific Ahr conditional knockout mice (nAhrCKO and aAhrCKO). By using chronic I3S treatment in primary astrocytes and glia‐neuron (GN) mix cultures to mimic the CKD brain microenvironment, we also found significant reduction of GLT1 expression and activity in an AhR‐dependent manner. Chronic I3S treatment induced AhR‐dependent pro‐oxidant Nox1 and AhR‐independent anti‐oxidant HO‐1 expressions. Notably, AhR mediates chronic I3S‐induced neuronal activity enhancement and synaptotoxicity in GN mix, not neuron‐enriched cortical culture. In CKD mice, neuronal activity enhancement was observed in ACC and hippocampal CA1, and these responses were abrogated by both nAhrCKO and aAhrCKO. Finally, intranasal AhR antagonist CH‐223191 administration significantly ameliorated the GLT1/PAPs reduction, increase in c‐Fos+ neurons, and memory impairment in the CKD mice. Thus, astrocytic AhR plays a crucial role in the CKD‐induced disturbance of neuron‐astrocyte interaction and mental disorders.
Main Points
CKD elevates brain I3S to activate astrocytic AhR, which mediates astrogliosis with GLT1 hypofunction and enhances neuronal activity in ACC and hippocampus.
Intranasal AhR antagonist administration ameliorates CKD‐induced brain/behavioral changes.
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