Id1 Promotes Tumor Cell Migration in Nonsmall Cell Lung Cancers

Id1, which belongs to the Id family of helix-loop-helix transcription factors has been most associated with tumor progression and metastatsis; however, its significance in lung cancers has not been extensively explored. Here we seek to evaluate the expression of Id1 in a pilot study of nonsmall-cell lung cancers (NSCLCs) and determine its diagnostic and functional significance in these tumors. Paired normal and malignant lung tissues as well as a panel of NSCLC primary tumors and cell lines were evaluated for Id1 expression using Western blotting and quantitative RT-PCR. Functional assays were performed to evaluate the role of Id1 in tumor cell growth, migration and progression. We find Id1 expression is upregulated in squamous cell carcinoma when compared to adenocarcinoma of the lung and that expression of Id1 versus the normal control is variable in NSCLCs. We also note that Id1 expression in NSCLC cells is largely growth factor dependant and constitutive expression of Id1 in NSCLC cells significantly increases tumor cell migration without affecting cell proliferation. We conclude that Id1, as a mediator of tumor cell migration, may be an indicator of aggressive potential in nonsmall-cell lung cancers

Dividends as Reference Points: A Behavioral Signaling Approach

We outline a dividend signaling model that features investors who are averse to dividend cuts. Managers with strong unobservable cash earnings separate by paying high dividends but retain enough to be likely not to fall short next period. The model is consistent with a Lintner partial-adjustment model; modal dividend changes of zero; stronger market reactions to dividend cuts than increases; comparatively infrequent and irregular repurchases; and a mechanism that does not depend on public destruction of value, which managers reject in surveys. New tests involve stronger reactions to changes from longer-maintained dividend levels and reference point currencies of ADR dividends

969-100 Changing Profile of the Cardiac Donor

AbstractAs the demand for organs for cardiac transplantation has increased, donor criteria have evolved. We reviewed the characteristics of 190 cardiac donors from 1983 to 1993 to identify trends in donor profile and to determine if recipient outcome were affected. Donors were divided into early(1983–1987; n=86) and late (1988-1993; n=104) groups according to operative era, While mean donor age has not changed significantly (24 ± 0.9 to 26 ± 1.3 years), the proportion of donors older than 40 years has increased from 1% (1/86) to 15% (16/104) (p<0.001). Trauma was the cause of death in 93% (80/86) of the early group and 65% of the late group (68/104) (p<0.001); in the total series, donors older than 40 years were less likely to have died from trauma 131%; 5/16) than younger donors (83%; 143/173) (p=0.001). The proportion of out-of-state donors has fallen from 71% (61/86) to 27% (28/104) (p<0.001), while the proportion of ethnic minorities increased from 10% (9/86) to 25% (26/1041 (p<0.001). There have been no significant changes in gender profile; males constituted 78% (67/86) of the early group and 72% (75/104) of the late group. Five year survival after transplant was not predicted by donor age, mode of donor death, recipient age, or recipient UNOS status. In summary, donors in the current era are more likely (1) to be older, (2) to be within the state, (3) to come from an ethnic minority, and (4) to have died from causes other than trauma when compared to donors from the earlier era

Importance of asymmetry and anisotropy in predicting cortical bone response and fracture using human body model femur in three-point bending and axial rotation

The final publication is available at Elsevier via https://dx.doi.org/10.1016/j.jmbbm.2018.07.033 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/Modeling of cortical bone response and failure is critical for the prediction of Crash Induced Injuries (CII) using advanced finite element (FE) Human Body Models (HBM). Although cortical bone is anisotropic and asymmetric in tension and compression, current HBM often utilize simple isotropic, symmetric, elastic-plastic constitutive models. In this study, a 50th percentile male femur FE model was used to quantify the effect of asymmetry and anisotropy in three-point bending and axial torsion. A complete set of cortical bone mechanical properties was identified from a literature review, and the femur model was used to investigate the importance of material asymmetry and anisotropy on the failure load/moment, failure displacement/rotation and fracture pattern. All models were able to predict failure load in bending, since this was dominated by the cortical bone material tensile response. However, only the orthotropic model was able to predict the torsional response and failure moment. Only the orthotropic model predicted the fracture initiation location and fracture pattern in bending, and the fracture initiation location in torsion; however, the anticipated spiral fracture pattern was not predicted by the models for torsional loading. The results demonstrated that asymmetry did not significantly improve the prediction capability, and that orthotropic material model with the identified material properties was able to predict the kinetics and kinematics for both three-point bending and axial torsion. This will help to provide an improved method for modeling hard tissue response and failure in full HBM.Honda R&D America

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling

Dapper, Dishevelled-associated antagonist of beta-catenin (DACT), is a key regulator of Wnt signaling pathway. The purpose of this study is to explore the epigenetic changes and the function of DACT2 in human gastric cancer (GC). Eight human gastric cancer cell lines, 167 cases of primary gastric cancer and 8 cases of normal gastric mucosa were involved in this study. In addition, methylation Specific PCR (MSP), semi-quantitative RT-PCR, colony formation assay, flow cytometry assay, siRNA, immunofluorescence techniques and xenograft mice models were employed. The results indicate that DACT2 is frequently methylated in human primary gastric cancer (55.7%), and that methylation of DACT2 is associated with lost or reduction in its expression (X-2 test, P<0.01). We found that DACT2 expression was regulated by promoter region hypermethylation. Methylation of DACT2 is associated with tumor differentiation, invasion and intravascular cancerous emboli (X-2 test, P<0.05, P<0.05 and P<0.05). In gastric cancer patients treated with 5-FU and cisplatin, the five-year survival rates are higher in DACT2 methylated cases. DACT2 inhibits cell proliferation, migration and invasion in gastric cancer cells and suppresses gastric cancer xenografts in mice. Restoration of DACT2 expression inhibits both canonical and noncanonical WNT signaling in SGC7901 cells. Restoration of DACT2 expression sensitized gastric cancer cells to paclitaxel and 5-FU. In conclusion, DACT2 is frequently methylated in human gastric cancer and DACT2 expression is silenced by promoter region hypermethylation. DACT2 suppressed gastric cancer proliferation, invasion and metastasis by inhibiting Wnt signaling both in vitro and in vivo.OncologySCI(E)[email protected]; [email protected]