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Abstract Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer without effective therapy. AMPK is downregulated in HCC and its activation diminishes tumor growth. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis, shows antitumor effects in different cancers. We aimed to study its putative action in liver-cancer derived cell lines through AMPK signaling. We performed cytometric studies for apoptosis and cell cycle, and 2D and 3D migration analysis in HepG2/C3A and Hep3B cells. ALA led to significant inhibition of cell migration/invasion only in HepG2/C3A cells. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced (shTP53) versus isogenic-TP53 HepG2/C3A cells. Furthermore, ALA inhibited epithelial-mesenchymal transition (EMT) in control HepG2/C3A but not in shTP53 nor in Hep3B cells. Besides, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival depending on TP53. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients.

Objective: Showcasing the Role of Digital Technologies, Frugal Innovation, and Imitability Attributes in Attracting Investments in Deep Tech Startups in an Emerging Economy. Methodology/approach: The primary data for this research were obtained from a sample of 216 deep tech startups from various sectors, located in São Paulo. The hypotheses were tested using structural equation modeling through the Partial Least Squares (PLS-SEM) method. Main results: Private investors are attracted to digital technologies and the attribute of being difficult to imitate. However, although there is a positive association between the capacity for frugal innovation and the hard-to-imitate attribute, no indirect effects of this capacity on investments were identified. Theoretical/methodological contributions: Focusing on emerging economies, this study contributes to the literature that investigates which factors explain investments in deep tech startups. Moreover, it contributes to the literature linking frugal innovation and technological complexity. Relevance/originality: Deep tech startups require substantial financial resources; however, in emerging markets, there is a scarcity of investment resources. Based on the RBV (Resource-Based View), this research demonstrates which capabilities are able to arouse the interest of private investors in the context of emerging economies. Social/management contributions: For entrepreneurs, the research highlights the importance of digital technologies in attracting investments. For investors and public policy makers, the study emphasizes the association of the capacity for frugal innovation with the attribute of imitability in deep tech startups.

Inovação é crucial para empresas competitivas, e sua implementação requer recursos financeiros substanciais. Tradicionalmente, fontes de financiamento como capital de risco e investidores-anjos são consideradas as mais adequadas. Em contrapartida, a dívida é considerada menos adequada devido aos riscos inerentes a inovação, criando-se uma associação negativa entre inovação e dívida. Ao mesmo tempo, a visão baseada em recursos enfatiza a importância dos recursos para a execução bem-sucedida da estratégia. Nesse sentido, este estudo trabalha com uma amostra de empresas americanas e examina dados do período entre 2008 e 2018, buscando identificar o efeito da interação da estratégia de inovação e dos recursos estratégicos no endividamento das empresas (estrutura de capital). Esse tópico é relevante uma vez que a dívida continua sendo uma fonte comum no financiamento da inovação, ainda que a literatura indique que ela seja inadequada para esse propósito. Os resultados mostram que uma empresa com estratégia de inovação e recursos estratégicos tem maior alavancagem.

Purpose: This article aims at the understanding of specific spaces where entrepreneurship education (EE) happens -- inside and outside the classroom. Design/methodology/approach: Building on frameworks such as formal versus non-formal entrepreneurial education and institutional versus non-institutional actors, this research applies structural equation modeling (SEM) to explore which spaces entrepreneurs attended as undergraduate students. Going beyond intentionality, the authors collected data from 175 respondents in Brazil, all of the respondents are entrepreneurs whose companies are at least one year old. Findings: Results demonstrate that student-led activities are as important as institutional ones when training future entrepreneurs, while specific in-classroom activities feature the lowest impact among the institutional ones. Research limitations/implications: Sample size and characteristics could impact the generalization power, but, since the results fit within research criteria, researchers can benefit by reflecting over new research horizons, going beyond classroom studies and understanding the university as an ecosystem of learning interventions. Practical implications: Results can be useful to university managers when designing institutional policies, fostering a diverse set of undergraduate experiences towards entrepreneurship training. Originality/value: Although current literature has focused on classroom education, researchers have been pointing out the need of stepping out of the classroom, analyzing other spaces such as student-led movements, co-curricular programs and more.

Purpose – This study aims to analyze the organizational learning capability relationship with operational performance and frugal innovation across Brazilian companies. Design/methodology/approach – Quantitative research was performed using collected data from 154 firms, which were analyzed using structural equation modeling. Findings – The results showed that organizational learning capability is an antecedent of frugal innovation. The results also predict a better operational performance for companies that actively innovate cost-effectively. Another result was the positive relationship between the organizational learning capability and the operational performance. The authors found that the indirect and positive relationship between organizational learning capability, frugal innovation and operational performance was confirmed, reinforcing the literature. Research limitations/implications – A theoretical implication of this study can be seen in the establishment of the relationship between organizational learning capability, frugal innovation and operational performance since no studies linking these variables together were found. Therefore, the organizational learning capability and the frugal innovation can be considered facilitators of the operational performance. Practical implications – Managers should consider organizational learning and frugal innovation when thinking about firms’ operational performance. In this way, to facilitate and achieve higher performance, it was found that organizational learning capability and frugal innovation have a great deal of impact on operational performance. Social implications – At frugal innovation, the needs of citizens are prioritized. It is a great instrument to face crises since it consists of developing simpler and cheaper products and services quickly, making them accessible to a larger group of consumers. Originality/value – This study seeks to understand whether Brazilian companies are moving toward a more frugal innovation strategy. The study opens the possibility of showing whether the organizational learning capability has also impacted this change.

Abstract Background In recent decades some studies described the frequent co-occurrence of celiac disease autoimmunity and overt celiac disease in patients with autism. Therefore, it was suggested that celiac disease could play a possible role in the etiopathogenesis of autism spectrum disorder. However, several other studies have not confirmed this association. The aim of the present study was to elucidate the potential association between autism spectrum disorder and celiac disease. Methods We prospectively collected data from an Italian cohort of 223 children at the time of their clinical diagnosis of autism spectrum disorder in the 2019–2020 period. A serological celiac disease screening was performed and data were available for 196 patients; male (M):female (F) ratio = 4.4:1; median age = 3.6 years; age range = 1.6–12.8 years. Full-blown celiac disease was established according to the diagnostic algorithm of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2012 or 2019 guidelines. Fisher’s exact test was used to compare the celiac disease seroprevalence and prevalence in our autism spectrum disorder cohort and in the Italian healthy pediatric population studied by Gatti et al. to highlight the possible differences between the two groups. Results A not statistically significant difference between the celiac disease seroprevalence in our autism spectrum disorder cohort (4.08%) and Gatti’s Italian healthy group (2.22%) was found, p = 0.0810; OR = 1.871. A similar result emerged for overt celiac disease prevalences (2.24% versus 1.58%, respectively), p = 0.2862; OR = 1.431. Conclusions Our data validates a weakness of association between autism spectrum disorder and celiac disease. On the basis of our results, a regular screening for CD in patients with ASD is not recommended to a greater extent than in the general population.

Background. Growing evidence suggests that bioactive compounds in berry fruits may mitigate inflammation in patients with chronic kidney disease (CKD). Objectives. To evaluate cranberry (Vaccinium macrocarpon) supplementation effects on modulation of transcription factors involved in inflammation and oxidative stress in nondialysis (stages 3 and 4) patients with CKD. Design/Participants. A randomized, double-blind, placebo-controlled study was performed with 30 patients to receive capsules containing cranberry extract (1000 mg/day) or placebo (1000 mg/day of corn starch) for two months. Measurements. The mRNA expression of nuclear factor-erythroid 2-related factor-2 (Nrf2) and nuclear factor-kB (NF-kB) was evaluated in peripheral blood mononuclear cells (PBMCs) by quantitative real-time polymerase chain reaction. Thiobarbituric acid reactive substances (TBARS) were measured in the plasma to assess oxidative stress. Interleukin-6 (IL-6) plasma levels were assessed by enzyme-linked immunosorbent assay and C-reactive protein (CRP) by immunoturbidimetric method. Results. Twenty-five patients completed the study: 12 in the cranberry group (56.7 ± 7.5 years and body mass index (BMI) of 29.6 ± 5.5 kg/m2) and 13 in the placebo group (58.8 ± 5.1 years and BMI 29.8 ± 5.4 kg/m2). There were no differences in NF-kB or Nrf2 mRNA expressions (p=0.99 and p=0.89) or TBARS, CRP, and IL-6 plasma levels after cranberry supplementation. Conclusions. The cranberry extract administration (1000 mg/day) did not affect Nrf2 and NF-kB mRNA expression, oxidative stress, or inflammatory markers levels in nondialysis CKD patients. This trial is registered with NCT04377919.

The use of e-learning services is growing in different contexts, especially in the COVID-19 pandemic. This study aims to examine students' acceptance of and intention to use Learning Management Systems (LMSs) for university education in Brazil using the extended technology acceptance model, unified theory of acceptance and use of technology (UTAUT), integrating quality construct adapted from the Service Quality Evaluation Model (ServQual). Examining a large sample (n = 1237) of students in Brazil through questionnaires, we investigate the behaviour of the users concerning the factors that influence the technology acceptance and the intention of the use in an e-learning system. Results show that intention to use an LMS is affected by the facilitating conditions (skilful, workable and easy to use), social influence (remarkable, preference for use and relevance), habit (routine, enjoyable and entertaining) and quality (reliable, tangibility, responsiveness and assurance), but not for effort expectancy (agility, knowledge and productivity). Our research findings suggest fostering replicate the model in different universities and countries understanding potential differences.

Objetivo: Este Caso de ensino tem como objetivo expor alunos de graduação e pós-graduação às problemáticas empresarias de tomada de decisão no desenvolvimento de estratégias de internacionalização. Dilema: Este caso de ensino aborda os dilemas de uma pequena empresa familiar brasileira ao tomar a decisão de internacionalização no mercado português. Uma empresa familiar de pequeno porte, que atua no setor de arquitetura, decoração e construção, na produção de obras personalizadas em rochas ornamentais, que se depara com a oportunidade de atender clientes no mercado português, depois de um longo período atuando apenas no mercado nacional. Relevância/originalidade: O caso se apresenta como uma oportunidade original e real para o professor trabalhar estratégias de internacionalização, revitalizando conceitos de proposta de valor, tomada de decisão, adequação de produtos e mercados e é indicado para aplicação em disciplinas de estratégia em cursos de graduação e pós-graduação.

Objective: This teaching case aims to expose undergraduate and graduate students to the business problems of decision-making in the development of internationalization strategies. Dilemma: This teaching case addresses the dilemmas of a small Brazilian family business when making the decision to internationalize in the Portuguese market. A small family business, which operates in the architecture, decoration, and construction sector, in the production of customized works in ornamental stones, which is faced with the opportunity to serve customers in the Portuguese market, after a long period operating only in the national market. Relevance/originality: The case presents itself as an original and real opportunity for the professor to work on internationalization strategies, revitalizing concepts of value proposition, decision-making, adequacy of products and markets and is indicated for application in strategy disciplines in undergraduate and graduate courses.

Resumo A visão baseada em capacidades é central ao entendimento de como ecossistemas podem ser gerenciados. No entanto, apesar da relevância deste tema, ainda existe uma lacuna na literatura sobre as capacidades necessárias à gestão de ecossistemas. O objetivo desse artigo é identificar e mapear as capacidades aplicadas à gestão de ecossistemas de negócios. A metodologia consistiu em uma revisão sistemática da literatura considerando duas bases de dados: Web of Science e Scopus. No total, foram analisados 789 trabalhos; destes 89 fizeram a ponte entre capacidades e ecossistemas. A análise de conteúdo foi realizada por meio de codificação, resultando em um agrupamento de 11 capacidades - uma foi dinâmica e as outras dez foram operacionais. Os resultados obtidos incluem identificação, mapeamento e estruturação das capacidades dinâmicas e operacionais para a gestão do ecossistema, bem como para sua dispersão entre seus atores: firma focal, fornecedores e complementadores. Desenvolvemos um framework de gestão das capacidades do ecossistema, o qual apresenta a capacidade dinâmica como elo central e impulsionador do conjunto das capacidades do ecossistema, que incluem as capacidades para: o seu alinhamento, a sua sustentação, o seu crescimento e sustentação das empresas nele. Contribuímos com a literatura e prática gerencial ao apresentar uma estruturação de capacidades para gestão do ecossistema, agrupadas em um framework que mostra as implicações da presença das diferentes capacidades no ecossistema. Também contribuímos ao apresentar sugestões de pesquisas futuras para cada agrupamento de capacidades.

الأهداف: تهدف هذه الدراسة إلى بيان كيفية توظيف الحديث الشريف وطريقة الاستدلال به، واستنباط الاختيارات والآراء الفقهية من خلاله، والوقوف على فهمه والمراد منه، عند مدرستي الشام والكوفة، عند الإمامين الأوزاعي وأبي حنيفة. المنهجية: من خلال الإمامين الأوزاعي وأبي حنيفة واللذين يعدَان من أبرز من يمثل تلك المدرستين. تم دراسة مسائل فقهية لأبواب مختلفة من صحيح البخاري، وتتبع أقوال الإمامين في تلك المسائل، وكيفية توظيفهما الحديث في استنباط الحكم الشرعي، وبيان وجه الدلالة منه. النتائج: توصلت الدراسة إلى نتائج أكدت على أهمية الحديث النبوي وأثره في استنباط الاختيارات والآراء الفقهية للإمامين الأوزاعي وأبي حنيفة، معتمدين على ذلك بأصولهما المذهبية الفقهية، ومناهجهما في الاستنباط، والتي أساسها القرآن والسنة والإجماع والقياس. الخلاصة: مدرستا الشام والكوفة من المدارس الحديثية التي بنت اختياراتها وأحكامها على الحديث الشريف استدلالا، واستنباطا. وتوصي الدراسة إلى ضرورة الاطلاع على مسالك فقهية أخرى لأئمة مذاهب في مدارس أخرى، والوقوف على مناهجهم في كيفية الاستدلال بالحديث الشريف، بالإضافة إلى بيان تكوينهم الفقهي من خلاله.

Alteration of metabolism in cancer cells is a central aspect of the mechanisms that sustain aggressive traits. Aldo–keto reductase 1 B1 (AKR1B1) catalyzes the reduction of several aldehydes to alcohols consuming NADPH. Nevertheless, the ability of AKR1B1 to reduce different substrates renders difficult to comprehensively ascertain its biological role. Recent evidence has implicated AKR1B1 in cancer; however, the mechanisms underlying its pro-oncogenic function remain largely unknown. In this work, we report that AKR1B1 expression is controlled by the p53 tumor suppressor. We found that breast cancer patients bearing wild-type TP53 have reduced AKR1B1 expression. In cancer cell lines, p53 reduced AKR1B1 mRNA and protein levels and repressed promoter activity in luciferase assays. Furthermore, chromatin immunoprecipitation assays indicated that p53 is recruited to the AKR1B1 promoter. We also observed that AKR1B1 overexpression promoted metastasis in the 4T1 orthotopic model of triple-negative breast cancer. Proteomic analysis of 4T1 cells overexpressing AKR1B1 showed that AKR1B1 exerts a marked effect on proteins related to metabolism, with a particular impact on mitochondrial function. This work provides novel insights on the link between the p53 pathway and metabolism in cancer cells and contributes to characterizing the alterations associated to the pathologic role of AKR1B1.

O presente artigo verifica as contribuições das incubadoras empresariais na gestão e criação do conhecimento em favor das empresas incubadas. Tem por objetivo compreender as contribuições citadas e analisar a influência do processo de incubação a partir do mapeamento de informações gerais sobre as instituições participantes deste estudo, assim como mecanismos, ferramentas e estruturas para a gestão e criação do conhecimento as quais podem alavancar o desenvolvimento sustentável de empresas que estão em estágio de estruturação. Apresenta pesquisa ancorada na revisão de literatura sobre incubadoras empresariais e gestão do conhecimento. Durante o processo de investigação, para avaliar e mapear os objetivos estabelecidos, a entrevista e, por conseguinte, o roteiro de entrevista foram utilizados como método e instrumento de coleta de dados, dentro de uma abordagem qualitativa. A partir disso, 3 empresas, dentre elas, um hub de conexões e duas incubadoras empresariais foram entrevistadas e suas respostas sistematizadas no estudo de caso múltiplo em questão. Sendo assim, a pesquisa realizada revelou que o processo de incubação proporciona e contribui de forma intensa com a criação e gestão do conhecimento às organizações incubadas ao desenvolver um ecossistema de inovação e fornecer mecanismos, estruturas e ferramentas que possibilitam o gerenciamento e desenvolvimento de novos conhecimentos nas organizações nascentes, além de vantagens competitivas.