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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.

Purpose: To investigate the effects of symbol format and verb argument structure on the naming, identification, and sentence generation in people with aphasia (PWA).Methods: A 2 × 2 randomized, mix...

Background: Drawing has long been a focus in aphasia research as a compensatory strategy for improving functional communication in individuals with aphasia, but fewer studies have addressed...

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., In this study, we used membrane proteomic analysis to identify that GPNMB is overexpressed and highly N‐glycosylated in the EGFR mutant, especially the EGFR‐L858R mutated, NSCLC. GPNMB could bind to mutated EGFR without ligand stimulation, activate its downstream signaling and promote cancer metastasis. N134 glycosylation of GPNMB also plays a crucial role in controlling this ligand‐independent regulation.

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.

Purpose The purpose of this study was to collect and analyze experiential narratives of clinicians from culturally and linguistically diverse (CLD) backgrounds and then disseminate the findings to ...

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.

Gastric cancer is the second most common cause of cancer related death worldwide and lacks a highly effective treatment for the advanced disease. In this study, we have successfully demonstrated the preparation of core–shell type biopolymer based zein/chondroitin sulphate nanoparticles for the delivery of sorafenib in gastric cancers. The SRF-loaded zein/chondroitin sulphate nanoparticles (SZCS) were nanosized with a spherical morphology and exhibited a higher encapsulation of more than >90%. The biopolymer nanoparticles showed the ability to release the drug in a controlled manner for 120 h, indicating their potential application in systemic delivery. The nanoparticles showed a remarkable uptake in gastric cancer cells in a time-dependent manner. The SZCS displayed an improved cytotoxic effect compared to that of free SRF in the equivalent concentrations in SGC7901 cancer cells. Also, we demonstrated a higher apoptosis and caspase 3/7 activity for the SZCS nanoparticle system. Based on our results, we can conclude that SZCS might hold great potential in the treatment of gastric cancers.

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.

Purpose: The purpose of this survey study was to examine the relationships between knowledge and training in evidence-based practice (EBP) and ethical decision-making processes among school based speech-language pathologists (SLPs) in the state of California, U.S.A. The possible factors that may prevent SLPs from making ethical clinical decision were also explored.Method: An online survey collected demographic information as well as responses pertaining to school-based SLPs’ understanding and implementation of EBP and ASHA Code of Ethics, and perceptions of possible constraints to ethical decision-making.Result: All demographic factors are not related to EBP implementation and ethical decision-making. Weak positive correlations were found between ethical decision-making and the use of research evidence as well as between EBP training and understanding the role of school-based SLPs. Factors that may have a notable impact on ethical decision-making include parent’s preference, school district policies, and lack of administrator’s support while caseload, workload, and service delivery model have relatively less impact.Conclusion: School-based SLPs who had the EBP training more likely incorporated EBP components during their decision-making process. However, the lack of comprehensive understanding of EBP and explicit guidelines of applying EBP to clinical practice may limit the effective implementation of EBP.

Despite advances in treatment and prognosis of non-small cell lung cancer (NSCLC), patient outcomes are still unsatisfactory.To reduce the morbidity and mortality of patients with NSCLC, a more comprehensive understanding of mechanisms involved in cancer progression is urgently needed.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.We identified Shisa3 as a novel tumor suppressor, which induces β-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 β-catenin degradation and was positively associated with overall survival and progression-free survival of NSCLC.Our results reveal that Shisa3 acts as a tumor suppressor by acceleration of β-catenin degradation and provide new insight for cancer prognosis and therapy.

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.

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.

To develop a theoretical, functional model of community navigation for individuals with cognitive impairments: the Activities of Community Transportation (ACTs).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.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.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.

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.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.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.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.

A compound parabolic concentrator (CPC) is proposed to mix light from RGBW LEDs. The designed CPC with an overall length of 49.6 mm and a concentration ratio of 17.3 achieves the efficiency of 95.2% in simulation. The proposed module has the merits of high efficiency and low cost.

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 μM suppressed Rstn mRNA levels by ∼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 μM 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.

Resistin (Rstn) is known as an adipocyte-specific secretory factor that can cause insulin resistance and decrease adipocyte differentiation. Conversely, based on various studies, insulin-like growth factors (IGFs) can improve insulin resistance and stimulate adipocyte adipogenesis. Whether IGFs exert their effects through the control of Rstn's production or modulation of Rstn's action is unknown. This study was designed to examine the influence and the signaling of IGF-I on Rstn gene expression and protein secretion by 3T3-L1 adipocytes. We found that IGF-I suppressed Rstn mRNA expression and protein release in dose- and time-dependent manners. The IC50 of IGF-I was ∼1 nM for a range of 6–10 h of treatment. Treatment with cycloheximide, but not with actinomycin D, prevented IGF-I-suppressed Rstn mRNA expression, suggesting that IGF-I destabilizes Rstn mRNA and that IGF-I's effect requires new protein, but not mRNA, synthesis. Pretreatment with IGF-I receptor (IGF-IR) antibody blocked IGF-I-altered IGF-IR activity and Rstn mRNA levels. Neither PD-98059, SB-203580, nor LY-294002 changed the IGF-I-decreased levels of Rstn mRNA, but they inhibited IGF-I-stimulated activities of MEK1, p38 MAPK, and phosphoinositide 3-kinase, respectively. However, SB-203580 antagonized the IGF-I-decreased Rstn protein release. These data demonstrate that IGF-I downregulates Rstn gene expression via IGF-IR-dependent and MEK1-, p38 MAPK-, and phosphoinositide 3-kinase-independent pathways and likely modifies the distribution of Rstn protein between the intracellular and extracellular compartments via a p38 MAPK-dependent pathway. Decreases in Rstn production and secretion induced by IGF-I may be related to the mechanism by which IGF-I modulates body weight and diabetes in animals.

This study sought to identify navigation patterns and illuminate the barriers to and possible solutions for independent community travel in people with chronic cognitive impairments as a result of acquired brain injury.Two investigative methods were used to explore navigation in the population of interest: Study 1 was a field study and study 2 convened a series of focus groups with relevant stakeholders.For study 1, each week during a 4 month period, researchers administered a navigational survey and structured interview to a typical case sample of six participants in order to catalogue all trips taken outside the assistive living facility. Study 2 convened six focus groups to access perspectives on navigational issues for individuals with cognitive impairments (CI) from a number of stakeholder groups including individuals with CI, care providers for this population and public transportation workers.The results of both studies were consistent and indicated that community access is severely restricted for individuals with CI. The majority of trips that were taken tended to be routine and assisted. The variety of travel was limited; participants ventured to the same set places with the same people. Participants described barriers accounting for these problems and suggested a number of strategies to minimize problems.

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.

A light-mixing module consisting of a compound parabolic concentrator (CPC) and a fiber for mixing light from red, green, blue, and white (RGBW) LEDs was proposed. The design principle was investigated and a design prototype was demonstrated in a simulation. The simulated results showed that the chromatic nonuniformity was reduced to 1/10 when the fiber length was 40 times the core width, and the module efficiencies were more than 80% and more than 60% when the fiber lengths were 350 mm and 5 m, respectively. The proposed module is suitable for solar lighting compensation or indoor lighting, such as plant-factory lighting.

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, EGCGinhibited the IGF-I-stimulated phosphorylation of the IGF-I receptor-beta (IGF-IR β), the association of IGF-IRwith the p66Shc protein, and the IGF-II-stimulated associations of the IGF-IIreceptor with Gαi-2 and p66Shc proteins, suggesting that EGCGselectively affects particular types of Shc and MAPKfamily members. Pretreatment with antiserum against the EGCGreceptor (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 EGCGon IGF-I- and IGF-II-stimulated ERK1/2 phosphorylation and subsequent preadipocyte proliferation. Conclusion The results of this study suggest that EGCGmediates anti-IGF-I and anti-IGF-IIsignals in preadipocyte mitogenesis via the 67LR but not the AMPKpathway.

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.

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-β, 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.

Sixty strains of Riemerella anatipestifer were isolated from ducks and geese with infectious serositis in Taiwan. Sixty per cent of the isolates (36/60) contained a 3.9 b plasmid, 12% (7/60) contained 6.5 b and 16 b plasmids, 5% (3/60) contained 2.9, 16 and 18 b plasmids and 13% contained no plasmid (14/60). The 3.9 b plasmid (designated as pCFC1) was completely sequenced to determine if it encoded virulence factors. pCFC1 was 27% G-C and had four large open reading frames (ORF). Two of the ORFs (designated as VapD1 and VapD2) encoded proteins that shared 80, 83, 69 and 67 (VapD1) and 50, 48, 21 and 20% (VapD2) identity with virulence-associated proteins of Actinobacillus Actinomycetemcomitans, Dichelobcater nodosus, Haemophilus influenzae and Neisseria gonorrheae, respectively. pCFC1 also had an ORF (designated as RepAl) that encoded a protein with approximately 30% identity to the RepA proteins of Neisseria gonorrhoeae, Campylobactor hyointestinalis and Pseudomonas aeroginosa. The region upstream of the RepA ORF had an A-T-rich region that was followed by four 21 bp perfect and one 20 bp imperfect direct repeat. The fourth ORF (designated as RepA2) encoded a protein with a region that was 44% homologous to the Helicobactor pylori replication protein.

Lung cancer is the leading cause of cancer related deaths worldwide. Delayed diagnosis and early metastasis are the major unsolved obstacles for most physicians in treating lung cancer patients. Thus, identifying novel metastatic genes and their action mechanisms involved in lung cancer progression and metastasis may provide new insights into the pathogenesis and management of lung cancer treatment. In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we identified a panel of 589 genes whose expression was correlated with cell invasiveness. And Inhibitor of DNA binding 4 (Id4) was one of these candidates. In this study, we demonstrate that the expression of Id4 was inversely associated with cell invasiveness in different lung cancer cell lines. Through manipulating the expression of Id4, we found that the expression of Id4 not only attenuate cell migration and invasion in vitro, but also affect the regulation of Epithelial-mesenchymal transition (EMT), a critical step for cancer metastasis. Additionally, we demonstrated that the expression Id4 was inversely correlated with lung cancer metastasis in vitro and in vivo and the reason Id4 affects metastasis probably is the regulation of EMT procession. Our data showed that Id4 could regulate EMT pathway by controlling the expression of Slug, a well-known EMT regulator, and recovering promoter activity of E-cadherin. Collectively, Id4 is a tumor suppressor in lung cancer, it can down-regulate EMT by reversing E-cadherin expression that represses by Slug. How to translate this research result for clinical application and develop potential therapeutic strategy for lung cancer treatment is our work in the future. Citation Format: Szu-Hua Pan, Yuan Ling Hsu, Pei-Fang Hung, Chia-Jen Wang, Chi-Chung Wang. Id4 inhibits cancer metastasis through EMT regulation in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1431. doi:10.1158/1538-7445.AM2015-1431

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.

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.

Green tea catechins, especially (−)-epigallocatechin gallate (EGCG), have been proposed as a chemopreventative for obesity, diabetes, cancer, and cardiovascular diseases. However, relatively little is known about the mechanism of the action of EGCG on fat cell function. This study was designed to investigate the pathways of EGCG's modulation of the mitogenesis of 3T3-L1 preadipocytes. Preadipocyte proliferation as indicated by an increased number of cells and greater incorporation of bromodeoxyuridine (BrdU) was inhibited by EGCG in dose-, time-, and growth phase-dependent manners. Also, EGCG dose and time dependently decreased levels of phospho-ERK1/2, Cdk2, and cyclin D1 proteins, reduced Cdk2 activity, and increased levels of G0/G1 growth arrest, p21waf/cip, and p27kip1, but not p18ink, proteins and their associations to Cdk2. However, neither MEK1, ERK1/2, p38 MAPK, phospho-p38, JNK, nor phospho-JNK was changed. Increased phospho-ERK1/2 content and Cdk2 activity, respectively, via the transfection of MEK1 and Cdk2 cDNA into preadipocytes prevented EGCG from reducing cell numbers. These data demonstrate the ERK- and Cdk2-dependent antimitogenic effects of EGCG. Moreover, EGCG was more effective than epicatechin, epicatechin gallate, and epigallocatechin in changing the mitogenic signals. The signal of EGCG in reducing growth of 3T3-L1 preadipocytes differed from that of 3T3 fibroblasts. Results of this study may relate to the mechanism by which EGCG modulates body weight.