Decreased Expression of Plakophilin-2 and αT-Catenin in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Markers for Diagnosis.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disease of the heart muscle. Clinical challenges remain, however, in identifying patients with ARVC in the early or concealed stages with subtle clinical manifestations. Therefore, we wanted to identify potential targets by immunohistochemical (IHC) analysis in comparison with controls. Pathogenic mutations were identified in 11 of 37 autopsied patients with ARVC. As observed from IHC analysis of the RV, expression of αT-catenin and plakophilin-2 is significantly decreased in autopsied patients with ARVC as compared to controls, and the decreased expression is consistent in patients with and without pathogenic mutations. Furthermore, ARVC specimens demonstrated a reduced localization of αT-catenin, desmocollin-2, desmoglein-2, desmoplakin, and plakophilin-2 on intercalated discs. These findings have been validated by comparing RV specimens obtained via endomyocardial biopsy between patients with ARVC and those without. The pathogenic mutation was present in 3 of 5 clinical patients with ARVC. In HL-1 myocytes, siRNA was used to knockdown CTNNA3, and western blotting analysis demonstrated that the decline in αT-catenin expression was accompanied by a significant decline in the expression of plakophilin-2. The aforementioned effect was directed towards protein degradation rather than mRNA stability. Plakophilin-2 expression decreases concurrently with the decline in CTNNA3 expression. Therefore, the expression of αT-catenin and plakophilin-2 could be potential surrogates for the diagnosis of ARVC.

N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC.

Lung cancer is the leading cause of cancer-related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild-type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non-metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non-small-cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR-mutated, especially EGFR-L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C-terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand-independent regulation. Depleting N134-glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N-glycosylated GPNMB in regulating the ligand-independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.

2-anilino-4-amino-5-aroylthiazole-type compound AS7128 inhibits lung cancer growth through decreased iASPP and p53 interaction.

Lung cancer is the leading cause of cancer-related death worldwide. Thus, developing novel therapeutic agents has become critical for lung cancer treatment. In this study, compound AS7128 was selected from a 2-million entry chemical library screening and identified as a candidate drug against non-small cell lung cancer in vitro and in vivo. Further investigation indicated that AS7128 could induce cell apoptosis and cell cycle arrest, especially in the mitosis stage. In addition, we also found that iASPP, an oncogenic protein that functionally inhibits p53, might be associated with AS7128 through mass identification. Further exploration indicated that AS7128 treatment could restore the transactivation ability of p53 and, thus, increase the expressions of its downstream target genes, which are related to cell cycle arrest and apoptosis. This occurs through disruption of the interactions between p53 and iASPP in cells. Taken together, AS7128 could bind to iASPP, disrupt the interaction between iASPP and p53, and result in cell cycle arrest and apoptosis. These findings may provide new insight for using iASPP as a therapeutic target for non-small cell lung cancer treatment.

Shisa3 is associated with prolonged survival through promoting ß-catenin degradation in lung cancer.

RATIONALE: Despite advances in treatment and prognosis of non-small cell lung cancer (NSCLC), patient outcomes are still unsatisfactory. OBJECTIVES: To reduce the morbidity and mortality of patients with NSCLC, a more comprehensive understanding of mechanisms involved in cancer progression is urgently needed. METHODS: By comparison of gene expression profiles in the cell line pair with differential invasion ability, CL1-0 and CL1-5, we found that Shisa3 was highly expressed in the low invasive cells. The effect of Shisa3 on invasion, migration, proliferation, apoptosis, epithelial-mesenchymal transition, and anchorage-independent growth activities in vitro and on tumor growth and metastasis in mice models were examined. The underlying mechanism of Shisa3 was explored by microarray and pathway analysis. Finally, the correlation of Shisa3 expression and clinical outcome was also calculated. MEASUREMENTS AND MAIN RESULTS: We identified Shisa3 as a novel tumor suppressor, which induces ß-catenin degradation resulting in suppression of tumorigenesis and invasion in vitro. Shisa3 decreased the tumor growth in mice with subcutaneous implantation and reduced the number of metastatic nodules in mice with tail vein injection and orthotopic implantation. Shisa3 performs the tumor suppression activity through WNT signaling predicted by microarray analysis. Our data found that Shisa3 accelerates ß-catenin degradation and was positively associated with overall survival and progression-free survival of NSCLC. CONCLUSIONS: Our results reveal that Shisa3 acts as a tumor suppressor by acceleration of ß-catenin degradation and provide new insight for cancer prognosis and therapy.

Idiom understanding in adulthood: examining age-related differences.

Idioms are figurative expressions such as hold your horses, kick the bucket, and lend me a hand, which commonly occur in everyday spoken and written language. Hence, the understanding of these expressions is essential for daily communication. In this study, we examined idiom understanding in healthy adults in their 20s, 40s, 60s and 80s (n=30 per group) to determine if performance would show an age-related decline. Participants judged their own familiarity with a set of 20 idioms, explained the meaning of each, described a situation in which the idiom could be used, and selected the appropriate interpretation from a set of choices. There was no evidence of an age-related decline on any tasks. Rather, the 60s group reported greater familiarity and offered better explanations than did the 20s group. Moreover, greater familiarity with idioms was associated with better understanding in adults.

Perceived Factors That Facilitate or Prevent the Use of Speech-Generating Devices in Bilingual Individuals With Aphasia.

PURPOSE: The aim of this study was to explore practicing speech-language pathologists' (SLPs') perceptions of factors that could facilitate or prevent the use of speech-generating devices (SGDs) in bilingual individuals with aphasia. Specifically, this exploratory study sought to identify the facilitators and barriers to SGD use in individuals with culturally and linguistically diverse backgrounds. METHOD: An online survey was distributed to SLPs through an e-mail listserv and social media of an augmentative and alternative communication company. This article focused on the results of the survey items related to (a) the presence of bilingual individuals with aphasia on an SLP's caseload, (b) training related to SGD or bilingual aphasia, and (c) barriers and facilitators to SGD use. A thematic analysis was conducted to analyze the barriers and facilitators to SGD use reported by the respondents. RESULTS: A total of 274 SLPs who met the inclusion criteria had experience in implementing SGD for people with aphasia. Regarding relevant training, our results indicated that very few SLPs received bilingual aphasia intervention training (17.22%) or bilingual SGD training (0.56%) in graduate school. The results from our thematic analysis revealed four major themes of barriers and facilitators to SGD use, including (a) hardware and software, (b) cultural and language content, (c) SLP's cultural and linguistic competency, and (d) resources. CONCLUSIONS: Practicing SLPs reported several barriers to SGD use in bilinguals with aphasia. Most notably, language barriers for monolingual SLPs were seen as the greatest barrier to language recovery in individuals with aphasia whose primary language is not English. Several other barriers were consistent with previous research, such as financial factors and insurance disparities. The top three most important factors that facilitate SGD use in bilinguals with aphasia, as identified by the respondents, include user-friendly symbol organization, personalized words, and ease of programming.

Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein.

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.

Green tea (-)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway.

Insulin and (-)-epigallocatechin gallate (EGCG) have been reported to regulate fat cell mitogenesis and adipogenesis, respectively. This study investigated the pathways involved in EGCG modulation of insulin-stimulated mitogenesis in 3T3-L1 preadipocytes. EGCG inhibited insulin stimulation of preadipocyte proliferation in a dose- and time-dependent manner. EGCG also suppressed insulin-stimulated phosphorylation of the insulin receptor-beta, insulin receptor (IR) substrates 1 and 2 (IRS1 and IRS2), and mitogen-activated protein kinase pathway proteins, RAF1, MEK1/2, and ERK1/2, but not JNK. Furthermore, EGCG inhibited the association of IR with the IRS1 and IRS2 proteins, but not with the IRS4 protein. These data suggest that EGCG selectively affects particular types of IRS and MAPK family members. Generally, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in modulating insulin-stimulated mitogenic signaling. We identified the EGCG receptor [also known as the 67-kDa laminin receptor (67LR)] in fat cells and found that its expression was sensitive to growth phase, tissue type, and differentiation state. Pretreatment of preadipocytes with 67LR antiserum prevented the effects of EGCG on insulin-stimulated phosphorylation of IRS2, RAF1, and ERK1/2 and insulin-stimulated preadipocyte proliferation (cell number and bromodeoxyuridine incorporation). Moreover, EGCG tended to increase insulin-stimulated associations between the 67LR and IR, IRS1, IRS2, and IRS4 proteins. These data suggest that EGCG mediates anti-insulin signaling in preadipocyte mitogenesis via the 67LR pathway.

Validation of the Activities of Community Transportation model for individuals with cognitive impairments.

PURPOSE: To develop a theoretical, functional model of community navigation for individuals with cognitive impairments: the Activities of Community Transportation (ACTs). METHODS: Iterative design using qualitative methods (i.e. document review, focus groups and observations). Four agencies providing travel training to adults with cognitive impairments in the USA participated in the validation study. RESULTS: A thorough document review and series of focus groups led to the development of a comprehensive model (ACTs Wheels) delineating the requisite steps and skills for community navigation. The model was validated and updated based on observations of 395 actual trips by travellers with navigational challenges from the four participating agencies. Results revealed that the 'ACTs Wheel' models were complete and comprehensive. CONCLUSIONS: The 'ACTs Wheels' represent a comprehensive model of the steps needed to navigate to destinations using paratransit and fixed-route public transportation systems for travellers with cognitive impairments. Suggestions are made for future investigations of community transportation for this population.

Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis.

BACKGROUND: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. METHODS: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. RESULTS: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. CONCLUSIONS: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.

17 beta-estradiol stimulates resistin gene expression in 3T3-L1 adipocytes via the estrogen receptor, extracellularly regulated kinase, and CCAAT/enhancer binding protein-alpha pathways.

Resistin is known as an adipocyte-specific secretory hormone that can cause insulin resistance and decrease adipocyte differentiation. It can be regulated by sexual hormones, but the mechanism of estrogen's actions is still not clear. Using 3T3-L1 adipocytes, we found that 17 beta-estradiol (E2) up-regulated resistin mRNA expression in a dose- and time-dependent manner. The concentration of E2 that increased resistin mRNA levels by 100-250% was approximately 1 nM for a range of 1-24 h of treatment. Treatment with either actinomycin D or cycloheximide prevented E2-stimulated resistin mRNA expression, suggesting that the effect of E2 requires new mRNA and protein synthesis. Although E2 was shown to increase activities of the estrogen receptor (ER) and MAPK kinase 1 and the association of nuclear ER alpha and CCAAT/enhancer binding protein-alpha with the resistin gene promoter, signaling was demonstrated to be blocked by pretreatment with either ICI182780 or PD98059. Neither SB203580 nor LY294002 changed the E2-increased levels of resistin mRNA, but they respectively inhibited E2-stimulated phosphorylation of p38 MAPK and Akt. These results imply the ER alpha, ERK, and CCAAT/enhancer binding protein- are necessary for the E2 stimulation of transcription from the resistin promoter. Moreover, PD98059, but not SB203580 or LY294002, antagonized E2-increased resistin protein release. These data suggest that E2 likely modifies the distribution of the resistin protein between the intracellular and extracellular compartments via an ERK-dependent pathway.

MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma.

Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin is a novel therapeutic target because it plays critical roles in cancer progression and exosome biogenesis. Here we show that Slug, a key epithelial-mesenchymal-transition (EMT) regulator, is a MDA-9/Syntenin downstream target. Mitogen EGF stimulation increases Slug expression and MDA-9/Syntenin nuclear translocation. MDA-9/Syntenin uses its PDZ1 domain to bind with Slug, and this interaction further leads to HDAC1 recruitment, up-regulation of Slug transcriptional repressor activity, enhanced Slug-mediated EMT, and promotion of cancer invasion and metastasis. The PDZ domains and nuclear localization of MDA-9/Syntenin are both required for promoting Slug-mediated cancer invasion. Clinically, patients with high MDA-9/Syntenin and high Slug expressions were associated with poor overall survival compared to those with low expression in lung adenocarcinomas. Our findings provide evidence that MDA-9/Syntenin acts as a pivotal adaptor of Slug and it transcriptionally enhances Slug-mediated EMT to promote cancer invasion and metastasis.

Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin.

Microtubule targeting agents (MTAs) constitute a class of drugs for cancer treatment. Despite many MTAs have been proven to significantly improve the treatment outcomes of various malignancies, resistance has usually occurred. By selection from a two million entry chemical library based on the efficacy and safety, we identified purine-type compounds that were active against lung small cell lung cancer (NSCLC). The purine compound 5a (GRC0321) was an MTA with good effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of katanin, which cut the cellular microtubules into short pieces and activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting effect of 5a is a unique mechanism in MTAs. It might overcome the resistance problems that most of the MTAs have faced.

The apoptotic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the Cdk2 pathway.

This study was designed to investigate the effect of green tea catechins, especially (-)-epigallocatechin gallate (EGCG), on the apoptosis of 3T3-L1 preadipocytes. Preadipocyte apoptosis as indicated by formation of DNA fragments was induced by EGCG in dose-dependent manners. While EGCG was demonstrated to decrease Cdk2 expression and activity and increase caspase-3 activity, overexpression of Cdk2 and treatment with the caspase-3 inhibitor respectively prevented preadipocytes from induction of DNA fragmentation and caspase-3 activity by doses of 100-400 muM of EGCG. This suggests the Cdk2- and caspase-3-dependent apoptotic effects of EGCG. Moreover, EGCG was more effective than EC, ECG, and EGC in changing the apoptotic signals. Results of this study may relate to the mechanism by which EGCG modulates body weight.

The motor protein KIF14 inhibits tumor growth and cancer metastasis in lung adenocarcinoma.

The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas.

Green tea (-)-epigallocatechin gallate inhibits IGF-I and IGF-II stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor, but not AMP-activated protein kinase pathway.

SCOPE: This study investigated the pathways involved in epigallocatechin gallate (EGCG) modulation of insulin-like growth factor (IGF)-I-stimulated and IGF-II-stimulated mitogenesis in 3T3-L1 preadipocytes. METHODS AND RESULTS: We found that this process was dose and time dependent, and caused by suppression of IGF-I-stimulated and IGF-II-stimulated phosphorylation of p66Shc and mitogen-activated protein kinase (MAPK) pathway proteins, including MEK1 kinase (RAF1), extracellular signal-regulated protein kinase (ERK) kinase (MEK1), and ERK 1 and ERK 2 (ERK1/2), but not phospho-Jun-N-terminal kinase, protein kinase B, p52Shc, or p46Shc. Furthermore, EGCG inhibited the IGF-I-stimulated phosphorylation of the IGF-I receptor-beta (IGF-IR ß), the association of IGF-IR with the p66Shc protein, and the IGF-II-stimulated associations of the IGF-II receptor with G(αi-2) and p66Shc proteins, suggesting that EGCG selectively affects particular types of Shc and MAPK family members. Pretreatment with antiserum against the EGCG receptor (also known as the 67-kDa laminin receptor; 67LR), but not with an adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, prevented the inhibitory actions of EGCG on IGF-I- and IGF-II-stimulated ERK1/2 phosphorylation and subsequent preadipocyte proliferation. CONCLUSION: The results of this study suggest that EGCG mediates anti-IGF-I and anti-IGF-II signals in preadipocyte mitogenesis via the 67LR but not the AMPK pathway.

The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1.

Metastasis is a predominant cause of death in patients with cancer. It is a complex multistep process that needs to be better understood if we are to develop new approaches to managing tumor metastasis. Tumor cell invasion of the local stroma is suppressed by collapsin response mediator protein-1 (CRMP-1). Recently, we identified a long isoform of CRMP-1 (LCRMP-1), expression of which correlates with cancer cell invasiveness and poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). Here, we report that LCRMP-1 overexpression in noninvasive human cell lines enhanced filopodia formation, cancer cell migration, and invasion via stabilization of actin. This effect required a highly conserved N-terminal region of LCRMP-1 as well as the WASP family verprolin-homologous protein-1/actin nucleation pathway (WAVE-1/actin nucleation pathway). Furthermore, LCRMP-1 appeared to act downstream of Cdc42, a Rho family protein known to be involved in actin rearrangement. In addition, LCRMP-1 associated with CRMP-1, which downregulated cancer cell metastasis by interrupting the association of LCRMP-1 and WAVE-1. Finally, we found that high-level expression of LCRMP-1 and low-level expression of CRMP-1 were associated with lymph node metastasis and poor survival in patients with NSCLC. In sum, we show that LCRMP-1 and CRMP-1 have opposing functions in regulating cancer cell invasion and metastasis and propose that this pathway may serve as a potential anticancer target.

Long form collapsin response mediator protein-1 (LCRMP-1) expression is associated with clinical outcome and lymph node metastasis in non-small cell lung cancer patients.

Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. We identified a novel human isoform of CRMP family proteins named long form CRMP-1 (LCRMP-1), which was different from the known invasion suppressor, CRMP-1, in its molecular weight and the N-terminal exon-1. This study was aimed to elucidate the clinical significance of LCRMP-1 in non-small cell lung cancer (NSCLC) patients. Full-length human LCRMP-1 was cloned from lung adenocarcinoma based on the Expressed Sequence Tags (EST) database. We generated LCRMP-1 specific antibody and subsequent in vitro and in vivo invasion assays showed positive correlations between LCRMP-1 expression and lung cancer cell invasiveness. We further demonstrated that high LCRMP-1 mRNA expressions were associated with poor overall and disease-free survivals (P=0.004 and 0.006, respectively, log-rank test) in 72 NSCLC patients. The results were confirmed in an independent cohort of 54 NSCLC patients by immunohistochemistry (P=0.032, log-rank test). The metastatic lymph nodes showed higher LCRMP-1 expressions as compared with the paired primary lung tumors (P=0.012, McNemar's test). In conclusion, LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in NSCLC.

A comparison of four prompt modes for route finding for community travellers with severe cognitive impairments.

PRIMARY OBJECTIVE: Navigational skills are fundamental to community travel and, hence, personal independence and are often disrupted in people with cognitive impairments. Navigation devices are being developed that can support community navigation by delivering directional information. Selecting an effective mode to provide route-prompts is a critical design issue. This study evaluated the differential effects on pedestrian route finding using different modes of prompting delivered via a handheld electronic device for travellers with severe cognitive impairments. RESEARCH DESIGN: A within-subject comparison study was used to evaluate potential differences in route navigation performance when travellers received directions using four different prompt modes: (1) aerial map image, (2) point of view map image, (3) text based instructions/no image and (4) audio direction/no image. METHODS AND PROCEDURES: Twenty travellers with severe cognitive impairments due to acquired brain injury walked four equivalent routes using four different prompting modes delivered via a wrist-worn navigation device. Navigation scores were computed that captured accuracy and confidence during navigation. MAIN OUTCOME: Results of the repeated measures Analysis of Variance suggested that participants performed best when given prompts via speech-based audio directions. The majority of the participants also preferred this prompting mode. Findings are interpreted in the context of cognitive resource allocation theory.

Inhibitory effect of green tea (-)-epigallocatechin gallate on resistin gene expression in 3T3-L1 adipocytes depends on the ERK pathway.

Resistin (Rstn) is known as an adipocyte-specific secretory hormone that can cause insulin resistance and decrease adipocyte differentiation. By contrast, green tea catechins, especially (-)-epigallocatechin gallate (EGCG), have been reported as body weight and diabetes chemopreventatives. Whether EGCG regulates production of Rstn is unknown. Using 3T3-L1 adipocytes, we found that EGCG at 20 and 100 microM suppressed Rstn mRNA levels by approximately 35 and 50%, respectively, after 3 h. The basal half-life of Rstn mRNA induced by actinomycin D was >12 h but shifted to 3 h in the presence of EGCG. This suggests that EGCG regulates the stability of Rstn mRNA. Treatment with cycloheximide did not prevent EGCG-suppressed Rstn mRNA levels, which suggests that the effect of EGCG does not require new protein synthesis. Intracellular Rstn protein significantly decreased in the presence of 100 microM EGCG 3 h after treatment, whereas the release of the Rstn protein did not significantly change. This suggests that EGCG may modulate the distribution of Rstn protein between the intracellular and extracellular compartments. EGCG did not affect the amounts of extracellular signal-related kinase-1/2 (ERK1/2), phospho-JNK, phospho-p38, and phospho-Akt proteins but reduced the amounts of phospho-ERK1/2 proteins. Overexpression with MEK1 blocked EGCG-inhibited Rstn mRNA expression. These data suggest that EGCG downregulates Rstn expression via a pathway that is dependent on the ERK pathway.