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Organizations are increasingly using teams to stimulate innovation. Often, these teams share knowledge and information with each other to help achieve their goals, while also competing for resources and striving to outperform each other. Importantly, based on their industry, the nature of work, or prior history, some teams may face more competition from peer teams than others. Our research examines how teams' competitive relations with other teams in the organization operate in tandem with their collaborative inter-team information exchange relations in impacting their innovation. Using two studies-a field study of 73 knowledge-intensive teams in high-tech engineering firms and a team-based network experimental study of 162 teams-we find that a high degree of overall competition with many peer teams reduces a focal team's ability to acquire and utilize diverse knowledge from these teams (i.e., inter-team knowledge integration), thereby hindering team innovation. However, applying insights from network structural hole theory, we find that when a focal team occupies a brokerage position in the inter-team information exchange network, this can help buffer the effects of competition in getting access to knowledge resources from other teams, thus enabling their innovation. Additionally, we find that focal broker teams' dealmaking and network obstruction behaviors explain these effects. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Voice-or the expression of ideas, concerns, or opinions on work issues by employees-can help organizations thrive. However, we highlight that men and women differ in their voice self-efficacy, or the personal confidence in formulating and articulating work-related viewpoints. Such differences, we argue, can impede women's voice from emerging at work. Drawing on social cognitive theory (SCT), we propose that women tend to develop greater voice self-efficacy and thereby speak up more when they have the opportunity to observe female rather than male leaders speak up. Hence, we point to the potential absence of women leaders who can role model speaking up at work as a likely inhibiter of women's voice. Using data from a correlational field study involving 368 employees and their leaders from a variety of industries in India and an experimental study in an online panel of 546 US-based workers, we found support for our hypotheses. We discuss the implications of our research for theory and practice. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Organizações , Autoeficácia , Feminino , Humanos , Aprendizagem , Masculino , Teoria PsicológicaRESUMO
PURPOSE: Breast cancer remains a prominent global disease affecting women worldwide despite the emergence of novel therapeutic regimens. Metastasis is responsible for most cancer-related deaths, and acquisition of a mesenchymal and migratory cancer cell phenotypes contributes to this devastating disease. The utilization of kinase targets in drug discovery have revolutionized the field of cancer research but despite impressive advancements in kinase-targeting drugs, a large portion of the human kinome remains understudied in cancer. NEK5, a member of the Never-in-mitosis kinase family, is an example of such an understudied kinase. Here, we characterized the function of NEK5 in breast cancer. METHODS: Stably overexpressing NEK5 cell lines (MCF7) and shRNA knockdown cell lines (MDA-MB-231, TU-BcX-4IC) were utilized. Cell morphology changes were evaluated using immunofluorescence and quantification of cytoskeletal components. Cell proliferation was assessed by Ki-67 staining and transwell migration assays tested cell migration capabilities. In vivo experiments with murine models were necessary to demonstrate NEK5 function in breast cancer tumor growth and metastasis. RESULTS: NEK5 activation altered breast cancer cell morphology and promoted cell migration independent of effects on cell proliferation. NEK5 overexpression or knockdown does not alter tumor growth kinetics but promotes or suppresses metastatic potential in a cell type-specific manner, respectively. CONCLUSION: While NEK5 activity modulated cytoskeletal changes and cell motility, NEK5 activity affected cell seeding capabilities but not metastatic colonization or proliferation in vivo. Here we characterized NEK5 function in breast cancer systems and we implicate NEK5 in regulating specific steps of metastatic progression.
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Neoplasias da Mama , Quinases Relacionadas a NIMA , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Humanos , Camundongos , Quinases Relacionadas a NIMA/genética , Fenótipo , RNA Interferente PequenoRESUMO
Breast cancer affects women globally; the majority of breast cancer-related mortalities are due to metastasis. Acquisition of a mesenchymal phenotype has been implicated in the progression of breast cancer cells to an invasive, metastatic state. Triple-negative breast cancer (TNBC) subtypes have high rates of metastases, recurrence, and have poorer prognoses compared to other breast cancer types, partially due to lack of commonly targeted receptors. Kinases have diverse and pivotal functions in metastasis in TNBC, and discovery of new kinase targets for TNBC is warranted. We previously used a screening approach to identify intermediate-synthesis nonpotent, nonselective small-molecule inhibitors from the Published Kinase Inhibitor Set that reversed the mesenchymal phenotype in TNBC cells. Two of these inhibitors (GSK346294A and GSK448459A) are structurally similar, but have unique kinase activity profiles and exhibited differential biologic effects on TNBC cells, specifically on epithelial-to-mesenchymal transition (EMT). Here, we further interrogate these effects and compare activity of these inhibitors on transwell migration, gene (qRT-PCR) and protein (western blot) expressions, and cancer stem cell-like behavior. We incorporated translational patient-derived xenograft models in these studies, and we focused on the lead inhibitor hit, GSK346294A, to demonstrate the utility of our comparative analysis as a screening modality to identify novel kinase targets and signaling pathways to pursue in TNBC. This study introduces a new method for discovering novel kinase targets that reverse the EMT phenotype; this screening approach can be applied to all cancer types and is not limited to breast cancer.
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Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Estrutura Molecular , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: This study aimed to investigate the role of the Quality Blue Primary Care (QBPC) program on healthcare utilization and overall cost among the beneficiaries of Blue Cross and Blue Shield of Louisiana (BCBSLA). STUDY DESIGN: Retrospective observational cohort study using claims data from adults residing in QBPC-implemented regions continuously enrolled through BCBSLA from June 2012 to December 2014 (N = 89,034). METHODS: Controlling for age, gender, and risk score by propensity score weighting, inpatient, outpatient, and corresponding medical expenditures were each compared between the QBPC group and the control group using a difference-in-differences regression model. RESULTS: Average total cost increased in both the QBPC and control groups in 2014, but the increase was significantly less in the intervention group-a difference of $27.09 per member per month (PMPM) (P ≤.001). Savings in total cost were derived largely from a decrease in hospitalizations-a difference of $18.85 PMPM (P = .0023). Furthermore, savings were associated with shifts in healthcare utilization by the intervention group toward proactive management, including increased primary care physician visits (P = .0106) and higher screening rates for diabetes (P = .0019). Inpatient admissions also decreased in the QBPC group, most significantly among those with chronic conditions (P <.05). Conversely, an unexpected increase was observed in emergency department visits. CONCLUSIONS: The QBPC program was associated with a shift in primary care delivery and reductions in overall cost. Savings were achieved largely through reductions in hospitalization costs.
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Planos de Seguro Blue Cross Blue Shield/economia , Assistência ao Paciente/economia , Atenção Primária à Saúde/economia , Qualidade da Assistência à Saúde/economia , Estudos de Coortes , Humanos , Louisiana , Reembolso de Incentivo/economia , Estudos Retrospectivos , Estados UnidosRESUMO
Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MEK5 pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5/ERK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents.
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MAP Quinase Quinase 5/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/uso terapêutico , Apoptose , Diferenciação Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , MAP Quinase Quinase 5/antagonistas & inibidores , MAP Quinase Quinase 5/genética , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
microRNAs (miRNAs) are small noncoding RNA molecules involved in the regulation of gene expression and play critical roles in human malignancies. Next-generation sequencing analysis of the MCF-7 breast cancer cell line overexpressing miR-335-5p and miR-335-3p demonstrated that the miRNA duplex repressed genes involved in the ERα signaling pathway, and enhanced resistance of MCF-7 cells to the growth inhibitory effects of tamoxifen. These data suggest that despite its conventional role in tumor suppression, the miR-335 transcript can also play an oncogenic role in promoting agonistic estrogen signaling in a cancerous setting.
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Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Tamoxifeno/farmacologia , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Purpose The aim of this study was to evaluate the reliability, construct validity and predictive validity of the Hong Kong Chinese version of the Orebro Musculoskeletal Pain Screening Questionnaire (COMPSQ-HK). Methods The COMPSQ-HK was developed using the forward-backward translation. Internal consistency was assessed using Cronbach's alpha and test-retest reliability was examined using intraclass correlation coefficient with one-way random-effects model (ICC1,1), minimum detectable change (MDC) and 95% limits of agreement (LoA). Construct validity was evaluated by correlating the COMPSQ-HK with the Numeric Pain Rating Scale, Roland-Morris Disability Questionnaire, Northwick Park Neck Pain Questionnaire, Tampa Scale for Kinesiophobia, and Medical Outcomes Study Short Form 12. The predictive validity was investigated using receiver operating characteristics (ROC) curve analyses with sick leave >60 days and return-to-work for ≥4 consecutive weeks as outcomes at 1 year follow-up. The areas under the curve (AUC) were calculated. Results The COMPSQ-HK was administered to 305 patients with acute/subacute low back pain and 160 patients with acute/subacute neck pain. The Cronbach's alphas and ICC1,1 ranged from 0.83 to 0.84 and 0.81 to 0.92 respectively. The MDC were 32.1 and 21.1. The 95% LoA were -32.4 to 31.8 and -15.4 to 26.7. The Pearson r ranged from 0.333 to 0.697 in absolute value. The AUC for the ROC curve analyses ranged from 0.59 to 0.71. Conclusions The COMPSQ-HK has good internal consistency, moderate test-retest reliability, satisfactory construct validity and predictive validity as a screening tool for patients with back and neck pain at risk of chronic disability.
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Avaliação da Deficiência , Dor Musculoesquelética/diagnóstico , Medição da Dor/métodos , Inquéritos e Questionários/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hong Kong , Humanos , Dor Lombar/classificação , Masculino , Pessoa de Meia-Idade , Cervicalgia/classificação , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Licença Médica/estatística & dados numéricos , TraduçõesRESUMO
Estrogen receptor alpha (ERα) signaling pathways are frequently disrupted in breast cancer and contribute to disease progression. ERα signaling is multifaceted and many ERα regulators have been identified including transcription factors and growth factor pathways. More recently, microRNAs (miRNAs) are shown to deregulate ERα activity in breast carcinomas, with alterations in both ERα and miRNA expression correlating to cancer progression. In this study, we show that a high expression of Argonaute 2 (AGO2), a translation regulatory protein and mediator of miRNA function, correlates with the luminal B breast cancer subtype. We further demonstrate that a high expression of AGO2 in ERα+ tumors correlates with a poor clinical outcome. MCF-7 breast cancer cells overexpressing AGO2 (MCF7-AGO2) altered ERα downstream signaling and selective ERα variant expression. Enhanced ERα-36, a 36 kDa ERα isoform, protein and gene expression was observed in vitro. Through quantitative polymerase chain reaction (qPCR), we demonstrate decreased basal expression of the full-length ERα and progesterone receptor genes, in addition to loss of estrogen stimulated gene expression in vitro. Despite the loss, MCF-7-AGO2 cells demonstrated increased estrogen stimulated tumorigenesis in vivo. Together with our clinical findings on AGO2 expression and the luminal B subtype, we suggest that AGO2 is a regulator of altered ERα signaling in breast tumors.
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Pleuropulmonary Blastoma (PPB) is the primary neoplastic manifestation of a pediatric cancer predisposition syndrome that is associated with several diseases including cystic nephroma, Wilms tumor, neuroblastoma, rhabdomyosarcoma, medulloblastoma, and ovarian Sertoli-Leydig cell tumor. The primary pathology of PPB, epithelial cysts with stromal hyperplasia and risk for progression to a complex primitive sarcoma, is associated with familial heterozygosity and lesion-associated epithelial loss-of-heterozygosity of DICER1. It has been hypothesized that loss of heterozygosity of DICER1 in lung epithelium is a non-cell autonomous etiology of PPB and a critical pathway that regulates lung development; however, there are no known direct targets of epithelial microRNAs (miRNAs) in the lung. Fibroblast Growth Factor 9 (FGF9) is expressed in the mesothelium and epithelium during lung development and primarily functions to regulate lung mesenchyme; however, there are no known mechanisms that regulate FGF9 expression during lung development. Using mouse genetics and molecular phenotyping of human PPB tissue, we show that FGF9 is overexpressed in lung epithelium in the initial multicystic stage of Type I PPB and that in mice lacking epithelial Dicer1, or induced to overexpress epithelial Fgf9, increased Fgf9 expression results in pulmonary mesenchymal hyperplasia and a multicystic architecture that is histologically and molecularly indistinguishable from Type I PPB. We further show that miR-140 is expressed in lung epithelium, regulates epithelial Fgf9 expression, and regulates pseudoglandular stages of lung development. These studies identify an essential miRNA-FGF9 pathway for lung development and a non-cell autonomous signaling mechanism that contributes to the mesenchymal hyperplasia that is characteristic of Type I PPB.
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RNA Helicases DEAD-box/metabolismo , Fator 9 de Crescimento de Fibroblastos/metabolismo , MicroRNAs/genética , Blastoma Pulmonar/genética , Ribonuclease III/metabolismo , Animais , RNA Helicases DEAD-box/genética , Modelos Animais de Doenças , Epitélio/patologia , Feminino , Fator 9 de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Pulmão/patologia , Masculino , Mesoderma/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Ribonuclease III/genética , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Here, we present PatMatch, an efficient, web-based pattern-matching program that enables searches for short nucleotide or peptide sequences such as cis-elements in nucleotide sequences or small domains and motifs in protein sequences. The program can be used to find matches to a user-specified sequence pattern that can be described using ambiguous sequence codes and a powerful and flexible pattern syntax based on regular expressions. A recent upgrade has improved performance and now supports both mismatches and wildcards in a single pattern. This enhancement has been achieved by replacing the previous searching algorithm, scan_for_matches [D'Souza et al. (1997), Trends in Genetics, 13, 497-498], with nondeterministic-reverse grep (NR-grep), a general pattern matching tool that allows for approximate string matching [Navarro (2001), Software Practice and Experience, 31, 1265-1312]. We have tailored NR-grep to be used for DNA and protein searches with PatMatch. The stand-alone version of the software can be adapted for use with any sequence dataset and is available for download at The Arabidopsis Information Resource (TAIR) at ftp://ftp.arabidopsis.org/home/tair/Software/Patmatch/. The PatMatch server is available on the web at http://www.arabidopsis.org/cgi-bin/patmatch/nph-patmatch.pl for searching Arabidopsis thaliana sequences.
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Peptídeos/química , Análise de Sequência de DNA/métodos , Análise de Sequência de Proteína/métodos , Software , Arabidopsis/genética , Proteínas de Arabidopsis/química , DNA de Plantas/química , Internet , Interface Usuário-ComputadorRESUMO
We describe multiple methods for accessing and querying the complex and integrated cellular data in the BioCyc family of databases: access through multiple file formats, access through Application Program Interfaces (APIs) for LISP, Perl and Java, and SQL access through the BioWarehouse relational database.