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Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors. In a retrospective analysis of data from four phase 3 clinical trials, elevated baseline serum IL-8 levels were associated with worse clinical outcomes in patients with multiple tumor types treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combinatorial therapy.

Purpose: Piwi-interacting RNAs (piRNAs) are a novel class of small non-coding RNAs, which are not easily degraded but detectable in human body fluids. Recent studies have shown that aberrant piRNA expression is a signature feature across multiple tumor types. However, the expressions of piRNAs in serum of tumor patients and their potential clinical values remain largely unclear. Patients and methods: High-throughput sequencing was performed to investigate the serum piRNA profiles, followed by evaluations in serum samples of 220 colorectal cancer (CRC) patients and 220 healthy controls using reverse transcription quantitative real-time PCR (RT-qPCR). Biomarker panels including piRNA-based Panel I and carcinoembryonic antigen (CEA)-based Panel II, were developed by logistic regression model, and their diagnostic potentials were compared. Fagan's nomogram was plotted to promote clinical application. Results: We identified five differentially expressed serum piRNAs (piR-001311, piR-004153, piR-017723, piR-017724 and piR-020365), which, when combined in the piRNA-based Panel I, outperformed the CEA-based Panel II (P

Aim Nivolumab, a fully human immunoglobulin G4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has activity in melanoma, non–small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), and Hodgkin lymphoma. Nivolumab is approved in the USA and EU for advanced melanoma, NSCLC, and RCC, and relapsed Hodgkin lymphoma in the USA. Programmed death-ligand 1 (PD-L1), a PD-1 ligand, is expressed on mononuclear leukocytes, myeloid cells, and tumor cells. PD-L1 is being investigated as a potential biomarker to predict the association of tumor PD-L1 expression with nivolumab efficacy. Methods Bristol-Myers Squibb and Dako previously reported on an automated PD-L1 immunohistochemical (IHC) assay that detects cell surface PD-L1 in formalin-fixed, paraffin-embedded, human tumor tissue specimens using Dako’s Autostainer Link 48. The primary antibody for this assay is a rabbit monoclonal antihuman PD-L1 antibody, clone 28-8. Another rabbit monoclonal antihuman PD-L1 antibody, clone E1L3N, was compared with 28-8 for specificity and sensitivity using an identical detection method followed by vendor-recommended detection methods. Results Using PD-L1 null clones of L2987 and ES-2 tumor cell lines, both antibodies were specific for detection of PD-L1 on the plasma membrane, although E1L3N also stained cytoplasm in ES-2 knockout cells. Using the identical method, E1L3N was slightly more sensitive than 28-8 based on staining intensities. Using manufacturer-recommended detection methods and predefined scoring criteria for plasma membrane staining of tumor and immune cells, 28-8 demonstrated significantly improved detection compared with E1L3N. Conclusions Epitope retrieval and highly sensitive detection reagents are key determinants in IHC detection of PD-L1. Electronic supplementary material The online version of this article (doi:10.1007/s40291-016-0237-9) contains supplementary material, which is available to authorized users.

To determine the relationships among retinal/choroidal thickness, retinal microvascular network and visual field in high myopia.This cross-sectional study included a total of 62 subjects, comprising 31 eyes with high myopia and 31 eyes with emmetropia or low myopia. Optical coherence tomography was used to quantify the thickness of ganglion cell complex (GCC), inner nuclear layer and outer plexiform layer (INOPL), outer retinal layer (ORL) and choroid layer (ChL). Optical coherence tomography angiography was used to quantify the superficial vessel density (SVD) and deep vessel density (DVD). Retinal light sensitivity (RLS) was measured by microperimetry-1 (MP1). The inner ring (1-1.75 mm), the outer ring (1.75-2.5 mm) and the whole ring (1-2.5 mm) around the macula were analysed and compared between the two groups. Pearson correlation analysis was performed to analyse the relationship among them.In the highly myopic group, the thinning of retinal/choroidal thickness and the decrease in retinal vessel density and RLS were found when compared to the emmetropia or low myopia (p 0.05). Decreased RLS was correlated with decreased ORL thickness (r = -0.469, p = 0.008) and choroid thickness (r = 0.398, p = 0.030). There was no correlation between retinal microvascular network parameters and RLS (p 0.05), but DVD showed a negative correlation with ORL (r = -0.474, p = 0.007).Early visual field defects in highly myopic eyes may be influenced by the ORL loss and defect of choroidal circulation. The deep retinal microvascular network may have a compensatory action in the hypoxic setting of high myopia.

Purpose To identify macular intraretinal layer changes of patients in remission from Behcet's disease (BD) of short and long duration and evaluate the associations with visual acuity (VA). Methods Thirty-two eyes from 26 BD patients were enrolled, including 16 eyes with a duration less than 3 years (0.5-2.5 years; BD1) and 16 eyes of longer duration (3-12 years; BD2). Their intraretinal layer thicknesses and integrity of ellipsoid zone (EZ) and interdigitation zone (IZ) were evaluated by spectral-domain optical coherence tomography (SD-OCT). Associations between VA and retinal structural changes were analyzed. Results Compared to controls, the inner retina was significantly thicker in BD groups, especially the nerve fiber layer (NFL). The outer retinal layer (ORL) was thicker in BD1 in the central and temporal regions and thinner in BD2 compared to controls in all regions. In BD2, there were more eyes with disruption of the EZ and IZ. Worsening VA was correlated with thickening of the NFL and inner nuclear layer (INL), thinning of the ORL, and greater disruption of the EZ and IZ. Multiple linear regression analysis revealed EZ disruption, nasal ORL, inferior NFL, and temporal and nasal INLs were independent predictors of best-corrected (BCVA). Conclusions Behcet's disease patients in remission had significant changes in the inner and outer retinal structures, associated with worse VA. Thickness and integrity of the intraretinal layers by SD-OCT and segmentation might be useful predictors for the degree of VA damage in BD remission.

In the current study, we explored the effects of ERPs (event-related potentials), related to the cross-modal transfer from visual input to phonological retrieval. Using Chinese single-character words, participants were asked to make orthographic (intra-modal) and phonological (cross-modal) responses to visually presented words. By comparing the cross-modal and intra-modal tasks, we found that both tasks evoke similar activity in the early stage of lexical processing, showing the same pattern of N2 effect (a negative component peaking around 220 ms) and P2 effect (a positive component peaking around 270 ms). However, the effect of the task was significant in the 300-700 ms time window, consisting of a frontal-based N400 effect and a parietal based late positive component (LPC) effect. These findings suggest that the frontal-based N400 is associated with orthography-to-phonology mapping in Chinese, and the LPC reflects greater requirement of maintaining retrieved information in working memory for the cross-modal processing. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Degradation of insulin was studied in this work. Casein and protamine could obviously suppress degradation of insulin by intestinal enzymes, and could protect insulin from degradation by the mechanism of competition and combination with proteolysis enzyme. What is more, co-incubated with HP-beta-CD-casein or HP-beta-CD-protamine, most insulin was protected from degradation by intestinal enzymes. In addition, it was found that the complexation of insulin with HP-beta-CD was characterized by UV absorption spectra. These results indicated that HP-beta-CD, casein and protamine could offer some positive and useful results, and could protect insulin from degradation during their transit through the intestinal tract.

The process of neovascularization from preexisting blood vessels, referred to as angiogenesis, plays a critical role in both tumor growth and dissemination in multiple cancer types. Currently, there exists a need to identify biomarkers that can both indicate biological activity and predict efficacy at the molecular level for antiangiogenesis drugs which are anticipated to result in tumor stasis rather than regression. To identify such biomarkers, athymic mice bearing L2987 human tumor xenografts were treated with the antiangiogenic agent brivanib alaninate, which is currently under clinical evaluation. This is an orally available and selective tyrosine kinase inhibitor that targets the key angiogenesis receptors vascular endothelial growth factor receptor 2 (VEGFR-2) and fibroblast growth factor receptor 1. In the described studies, tumor samples were collected from these xenografts and RNA was extracted for gene expression profiling on Affymetrix 430A mouse GeneChips. Statistical analysis was done using a defined set of genes identified to be coexpressed with VEGFR-2 from a clinical tumor gene expression profiling database and between tumor samples isolated from brivanib alaninate–treated and untreated mice. Tyrosine kinase receptor 1 (Tie-1), collagen type IV α1 (Col4a1), complement component 1, q subcomponent receptor 1 (C1qr1), angiotensin receptor–like 1 (Agtrl1), and vascular endothelial-cadherin (Cdh5) were all identified to be significantly modulated by treatment with brivanib alaninate. These genes, which may be potentially useful as markers of brivanib alaninate activity, were further studied at the protein level in two separate in vivo human colon tumor xenograft models, HCT116 and GEO, using immunohistochemistry-based approaches. [Cancer Res 2007;67(14):6899–906]

Background: Immunotherapy with PD-1 inhibitors is associated with increased survival in NSCLC. While PD-L1 expression enriches for clinical benefit, additional predictive biomarkers are critically needed to further define patient subsets associated with specific response/resistance profiles and to develop optimal combination strategies. We hypothesized that integration of pathology features derived from H&E and PD-L1 immunohistochemistry with genetic/genomic data from NSCLC could identify phenotypic/genotypic associations that highlight specific immunosuppressive mechanisms. Towards that end, we present data from an initial pilot analysis. Methods: Twenty-nine NSCLC (23 adenocarcinoma; 6 squamous cell carcinoma) were included. H&E-stained sections were scored for tumor grade (1-3), relative proportion of tumor stroma (stroma score 1-3), percent necrosis and intensity of chronic inflammatory infiltrate (1-3+). PD-L1 immunohistochemistry was performed using the DAKO 28-8 antibody. PD-L1 expression was scored in tumor cells by modified H-score and by the predominant pattern observed - diffuse, heterogeneous, tumor-stroma interface or negative, and in immune cells using a semi-quantitative intensity scale (1-3+). DNA and RNA extracts from FFPE tissue were subjected to whole exome sequencing and RNAseq from which mutation load, oncogene/tumor suppressor genotypes and inflammation signatures were derived. Results: The highest PD-L1 H-scores were associated with diffuse expression patterns and were observed in high grade tumors (Grade 3). Deleterious mutations in TP53, STK11, KEAP1, KRAS, EGFR and MET occurred at expected frequencies. These mutations occurred across multiple PD-L1 expression patterns except for STK11 which was restricted to PD-L1 negative tumors (p=0.077, Fisher exact test). STK11-mutant tumors also displayed a lower PD-L1+ inflammation score (p=0.046, Fisher exact test). Trends toward an increase in mutation load with increasing levels of chronic inflammation on H&E stain as well as with PD-L1+ chronic immune infiltrates were noted. Inflammation signatures derived from RNAseq showed an association between diffuse PD-L1 expression by IHC and the highest levels of inflammation mRNA signatures comprising T-cells (CD8, Tregs), B-cells, macrophages and MDSCs. Conclusions: The potential association between tumor grade, PD-L1 expression, intensity of the immune infiltrate and mutation load raise the possibility that tumor morphology predicts mutation load and associated immune response. The finding that STK11 mutation is restricted to PD-L1 negative tumors suggests an immunosuppressive mechanism is invoked in this setting. This dataset is currently being expanded to establish the significance of these findings. Citation Format: Robin Edwards, Patrik Vitazka, Peter Szabo, Han Chang, John Cogswell, Hao Tang, Kaushal Desai, Darren Locke, Qiuyan Wu, Joseph Szustakowski, Steven Bernstein, Michele Cleary. Cross-platform integrative analysis of NSCLC reveals association between PD-L1 expression patterns and tumor genetic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 593. doi:10.1158/1538-7445.AM2017-593

Meeting abstracts Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on lymphoid and non-lymphoid-derived cells that negatively regulates peripheral T-cell responses. PD-L1, the major PD-1 ligand, is expressed on various tumors and is being investigated as a possible predictive

The human neocortex appears to contain a dedicated visual word form area (VWFA) and an adjacent multimodal (visual/auditory) area. However, these conclusions are based on functional magnetic resonance imaging (fMRI) of alphabetic language processing, languages that have clear grapheme-to-phoneme correspondence (GPC) rules that make it difficult to disassociate visual-specific processing from form-to-sound mapping. In contrast, the Chinese language has no clear GPC rules. Therefore, the current study examined whether native Chinese readers also have the same VWFA and multimodal area. Two cross-modal tasks, phonological retrieval of visual words and orthographic retrieval of auditory words, were adopted. Different task requirements were also applied to explore how different levels of cognitive processing modulate activation of putative VWFA-like and multimodal-like regions. Results showed that the left occipitotemporal sulcus (LOTS) responded exclusively to visual inputs and an adjacent region, the left inferior temporal gyrus (LITG), showed comparable activation for both visual and auditory inputs. Surprisingly, processing levels did not significantly alter activation of these two regions. These findings indicated that there are both unimodal and multimodal word areas for non-alphabetic language reading, and that activity in these two word-specific regions are independent of task demands at the linguistic level.

Human epidermal keratinocytes synthesize a complex plasminogen activator proteolytic cascade, consisting of two plasminogen activating enzymes and two inhibitors, that is thought to play a role in epidermal migration and differentiation as well as in several cutaneous diseases. Quantification of the plasminogen activator cascade proteins in keratinocytes reveals that plasminogen activator inhibitor type 2 (PAI-2) is distinct from the other components (i.e., urokinase and tissue-type plasminogen activators and inhibitor type 1) in several respects: (i) PAI-2 remains mostly cell-associated, rather than secreted; (ii) The level of cell-associated PAI-2 is at least 50-fold greater than that of the other components; (iii) PAI-2 is the only component whose level is enhanced upon elevation of the Ca2+ concentration, which is well known to induce a more differentiated phenotype in keratinocyte culture. Immunocytochemical localization experiments reveal that most keratinocytes contain PAI-2, which in a subpopulation of more differentiated cells is resistant to detergent extraction. Additional immunocytochemical localization and immunoblot experiments demonstrate that some of the PAI-2 becomes incorporated into the cornified envelope during terminal differentiation of the keratinocyte. These studies raise the possibility that PAI-2 may have an intracellular role associated with the terminal stage of keratinocyte differentiation.

Background: The human folate receptor (FR) is selectively overexpressed in a number of human epithelial malignancies, including ovarian, renal, and prostate cancers. Folate-conjugated therapies provide a strategy for targeting patients with FR expressing tumors. Identification of patients with FR expressing tumors is important to increase the opportunity for clinical benefit from folate conjugated therapies. The goals of this study are to determine the prevalence of FRα expression in various solid tumors, and to determine the concordance of FRα expression between primary and matched metastatic tumors. This concordance could help to determine if primary tumor samples would be suitable for assessing FR expression in metastatic tumors. Little information on this is currently available. Methods: FRα expression was analyzed by immunohistochemistry (IHC) in 339 primary tumors covering a wide range of human tumor types. Concordance of FRα status in 86 archived primary and matched metastatic breast, renal, endometrial and ovarian tumors was assessed by IHC. Results: FRα expression prevalence was moderate to high in primary tumors of lung (13/29; 45%), renal (66/115; 57%), colon (17/27; 63%), prostate (8/12; 67%) and ovarian (22/29; 76%). FRα expression frequency was found relatively low in breast tumor (26/127; 20%) which is consistent with previous reports. Furthermore, for the first time, we showed a good concordance (81.4%) of FRα expression between paired primary and metastatic ovarian, endometrial, renal and breast malignancies. Conclusions: FRα is frequently overexpressed in ovarian, prostate, colon and renal tumors, suggesting these tumor patients might benefit more from folate conjugated therapies. New findings from this study show that FRα expression is maintained in metastatic tumors, indicating the utility of archived primary tumor samples for determining the FR positivity of metastatic tumors in patients receiving a folate conjugated agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3752.

Background A crucial event in Prostate Cancer progression is the conversion from a hormone-sensitive to a hormone-refractory disease state. Correlating with this transition, androgen receptor (AR) amplification and mutations are often observed in patients failing hormonal ablation therapies. β-Catenin, an essential component of the canonical Wnt signaling pathway, was shown to be a coactivator of the AR signaling in the presence of androgens. However, it is not yet clear what effect the increased levels of the AR could have on the Wnt signaling pathway in these hormone-refractory prostate cells. Results Transient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/β-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and β-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and β-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level. Conclusion Our findings suggest that the AR signaling through the Wnt/β-Catenin pathway should be added to the well established functional interactions between both pathways. Moreover, our data show that via this interaction the AR could promote prostate cell malignancy in a ligand-independent manner.