Characterization of a novel recombinant calcium-binding protein from Arca subcrenata and its anti-hepatoma activities in vitro and in vivo.

Previous studies demonstrated that ASP-3 was a novel calcium-binding protein from Arca subcrenata that effectively inhibited the proliferation of HepG2 cells. To further study the antitumor activity and mechanism of ASP-3, the cytotoxic effects of recombinant ASP-3 were evaluated in HepG2 cells. The results demonstrated that ASP-3 inhibited the proliferation of HepG2 cells by competitively binding to the EGF binding pocket of EGFR and inhibiting the JAK-STAT, RAS-RAF-MEK-ERK, and PI3K-Akt-mTOR signaling pathways mediated by EGFR. ASP-3 significantly inhibited tumor growth in a HepG2 cell subcutaneous xenograft nude mouse model, and its (25 mg/kg and 75 mg/kg) tumor inhibition rates were 46.92 % and 60.28 %, respectively. Furthermore, the crystal structure of ASP-3 was resolved at 1.4 Å. ASP-3 formed as a stable dimer and folded as an EF-Hand structure. ASP-3 stably bound to domain I and domain III of the EGFR extracellular region by using molecular docking and molecular dynamics simulation analysis. Compared with the endogenous ligand EGF, ASP-3 displayed a stronger interaction with EGFR. These experimental results indicated that recombinant ASP-3 possessed an effective anti-hepatoma effect. So, it might be a potential molecule for liver cancer therapy.

As startups no contexto da organização capitalista financeira e as subjetividades empreendedoras / Startups in the context of financial capitalist organization and entrepreneurial subjectivities / Startups en el contexto de la organización capitalista financiera y subjetividades emprendedoras

As startups são empresas que apresentam modelos de negócios marcados pela inovação, rapidez, flexibilidade e alta capacidade de adaptação aos mercados. Atuando em diferentes setores socioeconômicos, elas prometem criar e transformar produtos e serviços. A emergência e disseminação dessas empresas ocorrem em um momento histórico de mudanças iniciadas a partir de 1970 e marcadas pelas crises geradas com o esgotamento do paradigma da sociedade urbano industrial. No Brasil, o número desse modelo de negócio apresentou uma expansão expressiva, alcançando a marca de 13.374 nos últimos cinco anos. Atento a esse cenário, o objetivo desta pesquisa consistiu em compreender como sujeitos, grupos e instituições atribuem sentidos à experiência de trabalho nas chamadas startups. Na parte teórica, as condições sociais e econômicas que possibilitaram a emergência e disseminação das startups são analisadas em uma perspectiva crítica. A parte empírica, por sua vez, apresenta depoimentos de empreendedores relatando o contexto geral de atuação nas startups. Ao final deste artigo, conclui-se que há uma instrumentalização capitalística de componentes subjetivos específicos selecionados e colocados em circulação para fortalecer o modo de produção capitalista financeirizado.(AU)

Startups are companies that have business models characterized by innovation, speed, flexibility, and a high capacity to adapt to markets. Operating in different socioeconomic sectors, they promise to create and transform products and services. The emergence and dissemination of these companies occur at a historical moment of changes that began from 1970 and are marked by the crises generated by the exhaustion of the paradigm of industrial urban society. In Brazil, the number of businesses in this model showed a significant expansion, reaching 13,374 companies in the last five years. Attentive to this scenario, the objective of this research was to understand how subjects, groups, and institutions attribute meanings to the work experience in so-called startups. In the theoretical part, the social and economic conditions that enabled the emergence and dissemination of startups are analyzed in a critical perspective. The empirical part presents entrepreneurs reporting the general context of action in startups. At the end of this article, it is concluded that there is a capitalistic instrumentalization of specific subjective components that are selected and put into circulation to strengthen the financed capitalist production.(AU)

Las startups son empresas que tienen modelos de negocio marcados por la innovación, la velocidad, la flexibilidad y una alta capacidad de adaptación a los mercados. Desde diferentes sectores socioeconómicos, las startups prometen crear y transformar productos y servicios. La aparición y difusión de estas empresas se produce en un momento histórico de cambios que comenzó a partir de 1970 y que está marcado por crisis generadas por el agotamiento del paradigma de la sociedad urbana industrial. En Brasil, estas empresas se expandieron significativamente alcanzando la marca de 13.374 empresas en los últimos cinco años. En este escenario, el objetivo de esta investigación fue entender cómo los sujetos, grupos e instituciones atribuyen significados a la experiencia laboral en las startups. En la parte teórica, se analizan las condiciones sociales y económicas que permitieron el surgimiento y la difusión de las startups en una perspectiva crítica. La parte empírica presenta testimonios de emprendedores que informan sobre el trabajo en startups. La investigación concluye que hay una instrumentalización capitalista de componentes subjetivos específicos que se seleccionan y ponen en circulación para fortalecer el modo de producción capitalista financiero.(AU)

Medicare Durable Medical Equipment Competitive Bidding Program: An Evaluation.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) implemented the Medicare durable medical equipment (DME) Competitive Bidding Program (CBP) in 2011. Since then, concerns have been raised regarding access to equipment and adverse health outcomes. OBJECTIVES: The aim was to evaluate whether the CBP was associated with changes in spending, utilization, and adverse health events (emergency department visits, hospitalizations, and falls). RESEARCH DESIGN: A comparative interrupted time series over 8 years was used to compare Round1 and Round2 bidding to nonbidding areas. Medicare fee for services claims were aggregated at the quarterly Metropolitan Statistical Area (MSA) level from 2009 to 2016. RESULTS: For the 3 evaluated DME (continuous positive airway pressure machines, oxygen supplies, and walkers), we found that implementation of the Medicare CBP was associated with reductions in per capita spending without changes in DME utilization or adverse health outcomes in CBP areas compared with nonbidding areas. For example, the slope change in the proportion of oxygen supplies purchasers in Round1 areas after implementation of Round1 was similar to the slope change in nonbidding areas (-0.0002; 95% CI: -0.0004, 0.0001; P=0.189). The difference in slope changes of emergency department visits and hospitalization in Round1 areas for oxygen supplies were (-0.0004; 95% CI: -0.0016, 0.0008; P=0.514) and (0.0002; 95% CI: -0.0010, 0.0014; P=0.757), respectively. Findings in Round2 areas after implementation of Round2 were similar to findings in Round1 areas. CONCLUSIONS: The Medicare DME CBP lowered Medicare expenditures while not reducing beneficiary access or increasing adverse outcomes.

A nova lei de licitações como promotora da maldição do vencedor / La nueva ley de licitaciones como promotora de la maldición del ganador / The new Brazilian public procurement law as promoter of the winner's curse

Resumo Evitar sobrepreços e preços manifestamente inexequíveis são dois objetivos principais da recém-promulgada Lei nº 14.133, de 1º de abril de 2021. O presente artigo demonstra que, ao tentar alcançar o primeiro objetivo, a nova lei de licitações promove o segundo, pois um comando específico tende a reduzir os preços até congelá-los nos menores valores possíveis, conduzindo os contratados à maldição do vencedor. Alerta-se os agentes públicos sobre o fato de que a manutenção desse comando levará a descumprimentos generalizados de contratos e a uma eventual falência de competidores. O método Monte Carlo é utilizado para demonstrar que um mecanismo abrangente de pesquisa de preços evitará o problema e garantirá o efeito pretendido pela lei.

Resumen Evitar los sobreprecios y los precios manifiestamente inviables son dos de los principales objetivos de la recién promulgada Ley 14.133/2021 de Brasil. Este artículo demuestra que, al intentar lograr el primer objetivo, la nueva ley de licitaciones promueve el segundo, ya que un comando específico tiende a reducir los precios hasta congelarlos a los valores más bajos practicables, llevando a los contratados a la maldición del ganador. Se advierte a los funcionarios públicos que mantener este comando conducirá a incumplimientos generalizados de contratos y eventual quiebra de los competidores. Se utiliza el método Monte Carlo para demostrar que un mecanismo integral de investigación de precios evitará el problema y garantizará el efecto buscado por la ley.

Abstract Avoiding overpricing and irresponsible pricing are two central objectives of the recently enacted Law 14133/2021. This article shows that when trying to achieve the first objective, the new Brazilian public procurement law promotes the second, since a specific command reduces maximum prices until they freeze to the lowest possible values, leading the contractors to the winner's curse. Public officials are warned that maintaining this command will lead to widespread breaches of contracts and eventual bankruptcy of contractors. The Monte Carlo method is adopted to show that a comprehensive price database will avoid the problem and guarantee the effect intended by the law.

The protective effect of natural phenolic compound on the functional and structural responses of inhibited catalase by a common azo food dye.

In this research retrieval effects of natural yellow (NY) on the performance of carmoisine (CAR) inhibited bovine liver catalase (BLC) was studied using multispectral and theoretical methods. Kinetic studies showed that CAR inhibited BLC through competitive inhibition (IC50 value of 2.24 × 10-6 M) while the addition of NY recover the activity of CAR-BLC up to 82% in comparison with the control enzyme. Circular dichroism data revealed that NY can repair the structural changes of BLC, affected by CAR. Furthermore, an equilibrium dialysis study indicated that NY could reduce the stability of the CAR-catalase complex. The surface plasmon resonance (SPR) data analysis indicated a high affinity of NY to BLC compared to CAR and the binding of NY led to a decrease in the affinity of the enzyme to the inhibitor. On the other hand, fluorescence and molecular docking studies showed that the quenching mechanism of BLC by CAR occurs through a static quenching process, and van der Waals forces and hydrogen bonding play a crucial role in the binding of CAR to BLC. MLSD data demonstrated that NY could increase the binding energy of CAR-BLC complex from -7.72 kJ mol-1 to -5.9 kJ mol-1, leading to complex instability and catalase activity salvage.

Launching a CDMO in Brazil aiming to develop biopharmaceuticals for clinical trials

The innovation timeline is expensive, risky, competitive, time-consuming, and labor-intensive. In order to overcome such challenges and optimize financial resources, pharmaceutical companies nowadays hire contract development and manufacturing organizations (CDMO) to help them. Based on the experience acquired first from the development of two biopharmaceuticals, the Heterologous Fibrin Sealant and the Apilic Antivenom, and more recently, during their respective clinical trials; the Center for the Study of Venoms and Venomous Animals (CEVAP) proposed to the Ministry of Health the creation of the first Brazilian CDMO. This groundbreaking venture will assist in converting a candidate molecule - from its discovery, proof of concept, product development, up to pilot batch production - into a product. The CDMO impact and legacy will be immense, offering service provision to the public and private sector by producing validated samples for clinical trials and academic training on translational research for those seeking a position in pharmaceutical industries and manufacturing platforms.(AU)

Modulating the activity of right temporo-parietal junction increases bidding behavior in lottery contests.

Contest often involves bids that are higher than the Nash equilibrium, and overbidding behaviour closely relates to personal reasoning and judgement. The right temporo-parietal junction (rTPJ) plays an important role in social, cognitive and inference decision-making. In the present study, we investigated the effect of transcranial direct current stimulation (tDCS) of the rTPJ on overbidding behaviour by using a modified model-lottery contests task. Our results showed that participants that received cathodal-stimulation had significantly higher expenditure compared to participants that received anodal and sham stimulation. Cathodal-stimulation may reduce the participants' ability to infer other contestants' intention or may modulate the non-monetary utility of winning. Our data indicate that excitability of the rTPJ may contribute to overbidding behaviour.

Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS).

S100B, a biomarker of malignant melanoma, interacts with the p53 protein and diminishes its tumor suppressor function, which makes this S100 family member a promising therapeutic target for treating malignant melanoma. However, it is a challenge to design inhibitors that are specific for S100B in melanoma versus other S100-family members that are important for normal cellular activities. For example, S100A1 is most similar in sequence and structure to S100B, and this S100 protein is important for normal skeletal and cardiac muscle function. Therefore, a combination of NMR and computer aided drug design (CADD) was used to initiate the design of specific S100B inhibitors. Fragment-based screening by NMR, also termed "SAR by NMR," is a well-established method, and was used to examine spectral perturbations in 2D [1H, 15N]-HSQC spectra of Ca2+-bound S100B and Ca2+-bound S100A1, side-by-side, and under identical conditions for comparison. Of the 1000 compounds screened, two were found to be specific for binding Ca2+-bound S100A1 and four were found to be specific for Ca2+-bound S100B, respectively. The NMR spectral perturbations observed in these six data sets were then used to model how each of these small molecule fragments showed specificity for one S100 versus the other using a CADD approach termed Site Identification by Ligand Competitive Saturation (SILCS). In summary, the combination of NMR and computational approaches provided insight into how S100A1 versus S100B bind small molecules specifically, which will enable improved drug design efforts to inhibit elevated S100B in melanoma. Such a fragment-based approach can be used generally to initiate the design of specific inhibitors for other highly homologous drug targets.

[Multivariate and Bayesian Network Analyses of the Factors Causing Belief Conflicts That Deteriorate Teamwork and Cause Stress among Pharmacists during Proposals and Inquiries of Prescription].

Pharmacists working in collaboration with doctors are mainly involved in proposals and inquiries of prescription. At such times, belief conflicts are expected to deteriorate teamwork and induce stress. However, there is no strong evidence for this. To clarify factors resulting in belief conflicts, we conducted a survey among 594 pharmacists working at medical institutions in Gifu City and belonging to Gifu Pharmaceutical Association or Gifu Prefectural Society of Hospital Pharmacists between January 2019 and April 2019. The items of the survey were gender, place of employment, pharmacist working experience (years), awareness of "professional competencies for pharmacists" stated in Model Core Curriculum for Pharmacy Education -2015 version-, whether each item of "professional competencies for pharmacists" is applicable to himself/herself or not, whether teamwork deteriorates and stress occurs due to proposals and inquiries of prescription or not, and Assessment of Belief Conflict in Relationship-14 (ABCR-14). The recovery rate of the questionnaire was 50.3% and the valid response rate was 77.6%. Multiple logistic regression and Bayesian network analyses revealed that "I can empathize with a patient's feelings and emotions, but I experience difficulty with unfair criticism" commonly resulted in teamwork deterioration due to proposals of prescription. "Pharmacist working experience years (more than 10 years)" and "The other staff make unreasonable demands of me in the work" commonly resulted in stress. Thus, belief conflicts in therapeutic relationships result in teamwork deterioration and stress in prescription proposals.

Estrogenization of insulin by catecholestrogen produced high affinity autoantibodies and altered the normal function of insulin in type 1 diabetes.

AIMS: Insulin (Ins) covalently modified by catecholestrogens (CEs) was commonly found in diabetic patients who have developed insulin resistance. Estrogenization of insulin altered its molecular function and effect carbohydrates metabolisms in these patients. Insulin resistance is a common phenomenon in diabetes but the exact mechanism remains unknown. In this study, binding specificity and affinity of autoantibodies against estrogenized insulin (4-hydroxyestradiol-insulin; 4-OHE2-Ins) were assayed in the serum of type 1 diabetes (T1D) patients in order to explain the phenomena behind insulin resistance. MATERIALS AND METHODS: Specificity and affinity of autoantibodies from the sera of 66 T1D patients and 41 controls were analyzed by direct binding, competition ELISA and quantitative precipitin titration. Insulin was also estimated in the serum of T1D patients by ELISA. KEY FINDING: Estrogenized insulin (4-OHE2-Ins) exhibited high affinity and specificity to T1D autoantibodies in comparison to Ins (p < .05) or 4-OHE2 (p < .001). Estrogenization of insulin alters its interaction with the insulin receptor (IR). The affinity constant of 4-OHE2-Ins with the T1D autoantibodies was found to be 1.41 × 10-7 M. SIGNIFICANCE: Estrogenization of insulin by catecholestrogen makes these molecules highly antigenic and produced high-affinity autoantibodies in T1D patients. As a result, patients develop insulin resistance and presented this molecule as a potential biomarker for T1D.

Sucesso e insucesso nas licitações da modalidade pregão: revisão scoping review / Success and failure in bidding process for reverse auction modality: a scoping review

RESUMO: O pregão é uma das modalidades de licitação, instituído pela Lei 10.520/02, e tem sido amplamente utilizado em instituições públicas. Apesar dos benefícios desta modalidade serem muitos, existe um número considerável de insucessos nos procedimentos, de modo que os pregões podem terminar fracassados, desertos ou, até mesmo cancelados, anulados ou revogados. O objetivo desse artigo é avaliar na literatura quais os motivos de sucessos e insucessos de licitações na modalidade pregão por meio de uma revisão de literatura realizada através de Scoping Review, conforme a proposta do Joanna Briggs Institute, realizada através da pergunta "Quais os fatores de sucesso e/ou insucesso encontrados nas compras por licitação na modalidade pregão?", nas bibliotecas digitais Capes Periódicos e Scientific Electronic Library Online e na base de dados PubMed. (AU)

ABSTRACT: The reverse auction is one of the bidding modalities, which was instituted by Law 10,520/02 and has been widely used in public institutions. Although the benefits of this modality are many, there is a considerable number of failures in the procedures, so that the reverse auction sessions may fail, with no participants or even be canceled, nullified, or revoked. This article aims to evaluate in the literature the reasons for successes and failures of the bidding process for reverse auction modality through a Scoping Review, as proposed by the Joanna Briggs Institute. The research question was "What are the factors of success and/or failure found in bidding purchases for reverse auction modality?", and the databases used were Capes Journals, Scientific Electronic Library Online, and PubMed. (AU)

Low risk, high reward? Repeated competitive biddings with multiple winners in health care.

We study physiotherapy providers' prices in repeated competitive biddings where multiple providers are accepted in geographical districts. Historically, only very few districts have rejected any providers. We show that this practice increased prices and analyze the effects the risk of rejection has on prices. Our data are derived from three subsequent competitive biddings. The results show that rejecting at least one provider decreased prices by more than 5% in the next procurement round. The results also indicate that providers have learned to calculate their optimal bids, which has also increased prices. Further, we perform counterfactual policy analysis of a capacity-rule of acceptance. The analysis shows that implementing a systematic acceptance rule results in a trade-off between direct cost savings and service continuity at patients' usual providers.

Fatores que influenciaram as condutas dos pregoeiros do Centro de Lançamento da Barreira do Inferno (CLBI) / Factores que influenciaron las conductas de los pregoneros del Centro de Lanzamiento de la Barrera del Infierno (CLBI) / Factors influencing the behavior of auctioneers operating in public procurement by Barreira do Inferno Launching Center (CLBI)

Resumo Este artigo trata dos fatores que influenciaram as condutas dos pregoeiros do Centro de Lançamento da Barreira do Inferno (CLBI) na execução dos processos eletrônicos de compras. Seu objetivo principal é analisar os fatores preponderantes que influenciaram as condutas dos pregoeiros do CLBI na execução dos pregões eletrônicos. A pesquisa teve como referência os preceitos da teoria sobre compras, tendo como dimensões de análise os aspectos organizacionais, motivacionais e de conhecimento e habilidades. A principal ferramenta metodológica consistiu em entrevistas semiestruturadas com os pregoeiros. Como resultado, verificou-se que a falta de reconhecimento da importância estratégica da atuação dos pregoeiros, de dedicação exclusiva e de especialização dos compradores públicos foram os principais fatores que influenciaram o desempenho dos pregoeiros do CLBI.

Resumen Este artículo trata sobre los factores que influenciaron las conductas de los pregoneros del CLBI en la ejecución de los procesos electrónicos de compras. Su objetivo principal es analizar los factores preponderantes que influenciaron las conductas de los pregoneros del CLBI en la ejecución de los pregones electrónicos. La investigación tuvo como referencia los preceptos de la teoría sobre compras, y como dimensiones de análisis los aspectos organizacionales, motivacionales y los de conocimiento y habilidades. La principal herramienta metodológica consistió en entrevistas semiestructuradas con los pregoneros. Como resultado, se verificó que la falta de reconocimiento de la importancia estratégica de la actuación de los pregoneros, de dedicación exclusiva y de especialización de los compradores públicos fueron los principales factores que influenciaron en el desempeño de los pregoneros del CLBI.

Abstract This article aims to analyze the preponderant factors influencing the behavior of auctioneers working for the Barreira do Inferno Launching Center (CLBI) in electronic purchasing processes. The research used references from the theory of purchasing, analyzing organizational and motivational aspects, as well as aspects related to knowledge and abilities. Data was collected using semi-structured interviews with auctioneers. As a result, it was possible to identify that the main factors influencing the auctioneer's behavior at CLBI were the lack of recognition of the strategic importance of their role, lack of exclusive dedication and specialization.

How Procurement Judges The Value of Medical Technologies: A Review of Healthcare Tenders.

OBJECTIVES: Procurement's important role in healthcare decision making has encouraged criticism and calls for greater collaboration with health technology assessment (HTA), and necessitates detailed analysis of how procurement approaches the decision task. METHODS: We reviewed tender documents that solicit medical technologies for patient care in Canada, focusing on request for proposal (RFP) tenders that assess quality and cost, supplemented by a census of all tender types. We extracted data to assess (i) use of group purchasing organizations (GPOs) as buyers, (ii) evaluation criteria and rubrics, and (iii) contract terms, as indicators of supplier type and market conditions. RESULTS: GPOs were dominant buyers for RFPs (54/97) and all tender types (120/226), and RFPs were the most common tender (92/226), with few price-only tenders (11/226). Evaluation criteria for quality were technical, including clinical or material specifications, as well as vendor experience and qualifications; "total cost" was frequently referenced (83/97), but inconsistently used. The most common (47/97) evaluative rubric was summed scores, or summed scores after excluding those below a mandatory minimum (22/97), with majority weight (64.1 percent, 62.9 percent) assigned to quality criteria. Where specified, expected contract lengths with successful suppliers were high (mean, 3.93 years; average renewal, 2.14 years), and most buyers (37/42) expected to award to a single supplier. CONCLUSIONS: Procurement's evaluative approach is distinctive. While aiming to go beyond price in the acquisition of most medical technologies, it adopts a narrow approach to assessing quality and costs, but also attends to factors little considered by HTA, suggesting opportunities for mutual lesson learning.

Encomendas tecnológicas no Brasil: guia geral de boas práticas

Esta publicação tem por objetivo contribuir com o debate acerca das encomendas tecnológicas (ETECs) no Brasil. De forma mais específica, pretende-se apresentar os princípios gerais para sua gestão pública. Assim, trata-se de um texto dedicado, principalmente, aos gestores públicos voltados a aplicar o uso do poder de compra do Estado como instrumento de estímulo à inovação.

Possibilidades de uso das compras públicas para alavancar a inovação entre empresas fornecedoras

Em Possibilidades de uso das compras públicas para alavancar a inovação entre empresas fornecedoras, é descrito o trabalho de André Rauen e Bianca de Paiva, que, por meio de técnica estatística de quase-experimento, argumentam que a demanda do setor público, apesar de ser relevante para a geração de emprego e renda, não proporciona impacto sobre esforço tecnológico das firmas fornecedoras ­ esforço esse medido pelo quantitativo de pessoal ocupado em áreas científicas e tecnológicas no meio empresarial. Seus achados indicam que a revisão dos marcos legais de compras públicas no Brasil precisa levar em conta de que maneira um orçamento anual na casa das dezenas de bilhões de reais pode incentivar o setor privado a produzir mais inovação.