Search

Supplementary figure 1. Antitumor activity of tipifarnib in HRAS WT patient-derived xenograft models. Supplementary figure 2. Advaita gene set enrichment analysis. Supplementary figure 3. ENRICHR gene set enrichment analysis.

Supplementary Materials and Methods

Supplementary table 1. Top tipifarnib modulated genes used for ENRICHR GSEA.

Purpose:To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missense HRAS mutations.Patients and Methods:A total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program including HRAS. Those with missense HRAS mutations or STK11:rs2075606 received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-day treatment cycles. The primary endpoint was progression-free survival at 6 months (PFS6).Results:We identified 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11:rs2075606 carriers. In 21 patients enrolled in the study, 14 and 7 patients had missense HRAS mutations and STK11:rs2075606, respectively. The most frequently observed adverse events included fatigue (86%) and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as an STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. The overall response rate by intent-to-treat analysis was 24% (4 missense and one nonsense frameshift HRAS mutation); no response was observed in patients with urothelial carcinoma with wild-type HRAS tumors. Five responses were observed in 12 evaluable patients of 15 with tumors carrying HRAS mutations.Conclusions:Oral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatment-refractory urothelial carcinoma containing HRAS mutations.

Comparison of the somatic mutational landscape in our patient population with The Cancer Genome Atlas (TCGA) data

Supplementary Figure Legends

Heatmap showing genomic biomarkers found in all genetically screened patients (n = 224)

Ampliseq results for the enrolled patients (n = 21)

Purpose: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both and wild-type and mutant ERα by targeting cysteine 530 and enforcing antagonist conformation. H3B-6545 demonstrated preclinical high activity in breast cancer models with constitutively active ESR1 mutations (Furman C, SABCS 2020) and clinical activity in pretreated women with ER+ breast cancer (Hamilton EP, ASCO 2021). Patients and Methods: The primary objective of the phase II is to estimate the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and secondary objectives include safety. Results: 94 pts were treated with 450 mg daily, the recommended phase II dose: 11 in the phase I and 83 in the phase II parts of the trial. Patients and tumor characteristics were presented previously (Hamilton EP, ASCO, 2021). As of March 31, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), nausea (17%), fatigue (16%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (39%), hemoglobin decrease (38%), Lymphocytes decrease (37%), ALT increase (14%), AST increase (13%), bilirubin increase (12%), and creatinine increase (12%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 35% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in Table 1. CI: Confidence interval. N: total number of pts in full analysis set, used in PFS analysis. n: number of response-evaluable pts, used in ORR and CBR analysis. Efficacy estimates were consistent across the various subgroups. Responses were demonstrated in heavily pretreated pts, pts with visceral metastases, pts with constitutionally active ESR1 Y537S mutations, and in pts who received chemotherapy in the metastatic setting. Numerically higher response rate and longer PFS were observed in pts with ESR1 Y537s. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα. Table 1.Consistency of H3B-6545 activity across the key subgroupsEfficacyClinical CharacteristicORR % (95% CI)CBR % (95% CI)Median PFS mo (95% CI)Overall population (N=94, n=72)16.7 (8.9, 27.3)40.3 (28.9, 52.5)5.1 (3.2, 6.2)Liver and/or lung metastases (N=76, n=62)17.7 (9.2, 29.5)41.9 (29.5, 55.2)5.4 (1.8, 7.2)≥3 prior regimens (N=49, n=39)20.5 (9.3, 36.5)48.7 (32.4, 65.2)5.4 (3.5, 7.3)Prior chemotherapy (N=47, n=35)17.1 (6.6, 33.6)51.4 (34.0, 68.6)5.5 (3.6, 7.3)PgR+ (N=38, n=32)15.6 (5.3, 32.8)50.0 (31.9, 68.1)5.4 (2.0, 8.8)ESR1 clonal Y537S (N=10, n=10)30.0 (6.7, 65.2)60.0 (26.2, 87.8)7.3 (0.8, 11.2)ESR1 clonal D538G (N=19, n=17)0.0 (0.0, 19.5)35.3 (14.2, 61.7)5.4 (1.7, 7.2) Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Aki Morikawa, E Claire Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail S Wright, Fadi Kayali, Lisa Cantagallo, Manav Korpal, Jenny Long, Jianjun Xiao, Benoit Destenaves, Lei Gao, Tarek Sahmoud, Antonio Gualberto, Dejan Juric. H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-10.

Background: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both mutant and wild-type ERα by targeting cysteine 530 and enforcing antagonist conformation. It demonstrated a manageable safety profile and single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (pts) (Hamilton et al, ASCO, 2021). Methods: The study aims at determining the recommended phase II doses of the combination of H3B-6545 and palbociclib in pts with ER+, HER2- mBC. Other endpoints include safety, pharmacokinetics, and preliminary efficacy. The escalation phase enrolls pts with at least 2 prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor are allowed. Each cohort enrolled 6 pts to ensure availability of sufficient PK data. During the first cycle, H3B-6545 was added to palbociclib on day 9. Dose-limiting toxicities (DLTs) were assessed during the first 28 days starting from the 1st day of adding H3B-6545 to palbociclib (cycle 1 day 9 to cycle 2 day 8). Both drugs were started on day 1 of each of the subsequent cycles. Results: As of June 15, 2021, 14 pts were enrolled: 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 7 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). Median age was 61 years (range: 28-75 years), ECOG performance status was 0 in 7 pts (50%) and 1 in 7 pts (50%) and 9 pts (64%) had lung and/or liver metastases. Median number of prior therapies in the metastatic setting was 3 (range: 1-6). Prior therapy in the metastatic setting included fulvestrant (93%), CDK4/6 inhibitors (79%), aromatase inhibitors (64%), and chemotherapy (29%). One pt in each Cohort was not evaluable for dose limiting toxicity (DLT) assessment and no DLTs were observed in the first 2 Cohorts. Seven pts discontinued study treatment because of progression and 1 pt discontinued due to diagnosis of a second primary cancer during the first cycle. Non-hematological grade 2 or higher adverse events (AE), irrespective of causality, reported in ≥2 pts were: nausea, vomiting, abdominal pain, and bone pain, each observed in 2 pts (14%). Gr. 1 and 2 sinus bradycardia were reported in 6 (43%) and 1 pts (7%), respectively. One pt (7%) had grade 1 QT prolongation. No grade 4 AEs or treatment-related deaths were reported. For hematology and chemistry laboratory abnormalities: gr. 3 and 4 neutropenia in 7 pts (50%) and 2 pts (14%), respectively, gr. 3 thrombocytopenia in 1 pt (7%), gr. 3 anemia in 2 pts (14%). Grade 2 decrease in estimated glomerular filtration rate was observed in 7 pts (50%), all reported irrespective of causality. Co-administration of palbociclib had no meaningful impact on H3B-6545 exposure (15% and 21% increase in geometric means of AUC and Cmax, respectively). Co-administration of H3B-6545 modestly increased palbociclib exposure (49% and 36% increase in geometric means of AUC and Cmax, respectively). Among 6 response-evaluable pts in Cohort 1, 2 pts (33%) had confirmed partial responses and 4 pts (67%) had stable disease. Both responding pts received prior therapy with a CDK4/6 inhibitor and fulvestrant. Cohort 2 efficacy data is not yet mature. Recruitment is currently ongoing in Cohort 3 (H3B-6545 450 mg QD and palbociclib 125 mg QD). Conclusions: The combination of H3B-6545 (up to 300 mg dose) and palbociclib (up to 125 mg dose) was well-tolerated and demonstrated preliminary anti-tumor activity in heavily pretreated pts with ER+, HER2- mBC. ClinicalTrials.gov Identifier: NCT04288089. Citation Format: Stephen Johnston, Timothy J Pluard, Judy S Wang, Erika P Hamilton, Dejan Juric, Catherine R Scholz, Elizabeth Hnitecki, Sara Dar, Lei Gao, Lisa Cantagallo, Manav Korpal, Jianjun Alan Xiao, Lihua Yu, Tarek Sahmoud, Antonio Gualberto. H3B-6545 in combination with palbociclib in women with metastatic estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, phase 1b study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-03.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

PURPOSEMutations in the HRAS (m HRAS) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M m HRAS HNSCC.METHODSWe enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.RESULTSOf the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).CONCLUSIONTipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist ( NCT02383927 ).

We aimed to investigate the relationship between workforce [força de trabalho (FT)] and earnings management in the Brazilian capital market and, additionally, identify whether operating activities management is a substitute for management by accruals. Evidence of the effect of the FT on earnings management practice is controversial, sometimes showing an effect on the reduction or smoothing of profit or even no effect. In Brazil, there are no studies that investigate how the intensity of the FT affects the managers’ behavior regarding the manipulation of profit. The research is relevant to the regulatory bodies because it brings empirical evidence of the incentives generated by the pressure of the FT so that the top executives reduce the result of the period, in a substitute way, to the manipulation of the company's operational activities. In addition, it is relevant for users of accounting information, as it demonstrates that the FT influences the recognition of results, affecting the quality of accounting information. The findings may assist regulatory bodies and investors, as it demonstrates that pressure from the FT is an important incentive for decision-making by executives and workers at the operating levels of companies and can support the improvement of labor regulations. Following Pae (2005), we use Jones' modified model (1991) with lagged accruals to detect earnings management. To capture the FT intensity, we employed the proxies presented by Hilary (2006) and a variable calculated from the statement of value added [demonstração do valor adicionado (DVA)]. We analyzed 119 companies listed on the Brazilian stock exchange during the period 2012-2018. It were found that the intensity of the FT negatively influences earnings management by accruals [gerenciamento de resultados por accruals (GRA)], expanding the evidence on the effects of workers' bargaining power on accounting choices. RESUMO Analisamos a relação entre força de trabalho (FT) e gerenciamento de resultados no mercado de capitais brasileiro e, adicionalmente, identificamos se o gerenciamento das atividades operacionais é um substituto do gerenciamento por accruals. As evidências do efeito da FT na prática do gerenciamento de resultados são controversas, às vezes elas mostram efeito na redução ou suavização do lucro ou até nenhum efeito. No Brasil, não há estudos que investiguem como a intensidade da FT afeta o comportamento dos gestores quanto ao gerenciamento do lucro. A pesquisa se mostra relevante para os órgãos reguladores porque traz evidências empíricas dos incentivos gerados pela pressão da FT para que os altos executivos reduzam o resultado do período, de maneira substitutiva, com vistas ao gerenciamento das atividades operacionais da empresa. Além disso, ela se mostra relevante para os usuários das informações contábeis, pois demonstra que a FT influencia o gerenciamento dos resultados, afetando a qualidade das informações contábeis. Os achados podem ser úteis para órgãos reguladores e investidores, pois demonstram que a pressão da FT é um importante incentivo para a tomada de decisões de executivos e trabalhadores nos níveis operacionais das empresas e pode subsidiar o aprimoramento das regulamentações trabalhistas. Seguindo Pae (2005), usamos o modelo modificado de Jones (1991) com accruals defasados para detectar o gerenciamento de resultados. Para captar a intensidade da FT, usamos as proxies apresentadas por Hilary (2006) e uma variável calculada a partir da demonstração do valor adicionado (DVA). Analisamos 119 empresas negociadas na bolsa de valores brasileira durante o período 2012-2018. Verificou-se que a intensidade da FT influencia negativamente o gerenciamento de resultados por accruals (GRA), ampliando as evidências dos efeitos do poder de negociação dos trabalhadores nas escolhas contábeis.

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-18T17:33:23Z No. of bitstreams: 1 5355-Texto do Artigo-23902-1-10-20210301.pdf: 413738 bytes, checksum: c5c3afc351f2abe36f84a3a674c7dfe8 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-06-21T19:22:38Z (GMT) No. of bitstreams: 1 5355-Texto do Artigo-23902-1-10-20210301.pdf: 413738 bytes, checksum: c5c3afc351f2abe36f84a3a674c7dfe8 (MD5) Made available in DSpace on 2021-06-21T19:22:38Z (GMT). No. of bitstreams: 1 5355-Texto do Artigo-23902-1-10-20210301.pdf: 413738 bytes, checksum: c5c3afc351f2abe36f84a3a674c7dfe8 (MD5) Previous issue date: 2021-03-01 Ministério da Ciência, Tecnologia, Inovações e Comunicações (MCTIC) O presente estudo realizou uma revisão sistemática da produção acadêmica acerca do Exame Nacional de Desempenho de Estudantes na área de Contabilidade e, para tanto, explorou os seguintes objetivos específicos: (i) escanear os periódicos nacionais com maior classificação no Qualis – CAPES; (ii) analisar quantitativa e qualitativamente os artigos localizados, incluindo a verificação de indicadores bibliométricos propostos na literatura; (iii) sintetizar graficamente a evolução da produção sobre esse tópico no período. O método de análise foi descritivo e bibliométrico, abarcando mais de dez anos de produção acadêmica sobre o ENADE em periódicos nacionais, além de teses de doutorado em Ciências Contábeis. Identificou-se um crescimento da produção sobre o ENADE nos últimos anos. Os achados referentes a indicadores bibliométricos específicos mostram que as Leis de Lotka, Bradford e Zipf são ratificadas. Ao final, é apresentado um quadro geral da produção acadêmica sobre o ENADE em mais de uma década, fornecendo indicativos de tendência para a pesquisa na área. Chapecó

RATIONALE: Addition of CDK 4/6 inhibitors to endocrine therapy has become standard for patients (pts) with ER+ and HER2- BC with improvements in overall survival. However, acquired resistance to front-line therapy is inevitable, and response to later-line therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα). H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). METHODS: PK samples in phase I were obtained at day 1 and day 15 of cycle 1 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose) and sparse PK samples were collected in the phase II part of the trial. For pts enrolled in the food effect sub-study of phase II, plasma samples were collected during cycle 1 on day 15 and day 22 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose). Nonlinear mixed effect model (NONMEM) was applied for development of population PK models to fit H3B-6545 plasma concentration data with NONMEM® version 7.4 software. R was used for data management, visualization and statistical summaries. RESULTS: This phase I-II trial enrolled 47 pts in phase I part and 83 pts in the phase II part at the recommended phase II dose of 450 mg QD as of May 15, 2020. The 1180 plasma concentrations of H3B-6545 from a total of 103 pts at doses of 100-600 mg available as of January 15, 2020 were included in this analysis, with the following characteristics [n or (median, min-max) unit]: race (n=91/5/1/6 for White/Black/Asian/others), age (62.5, 31-81) yrs, body weight (79.5, 49-140) Kg, BMI (26.9, 17.6-45.6) Kg/m2, albumin (40, 29-52) g/dL, ALP (88.5, 39-917) IU/L, ALT (28, 10-193) IU/L, AST (36.5, 13-259) IU/L, bilirubin (8.6, 1.7-25.7) µM and creatinine clearance (112, 49.5-389) mL/min. The median number of prior therapy in the metastatic setting was 3 (range: 1 - 10). Out of 103 patients, 32 pts received treatment with a single high-fat meal to test food effect on PK over a randomized crossover design. H3B-6545 plasma concentrations were best described with a one compartment disposition PK model, plus a combined first- and zero-order parallel absorption and lag time. The estimated apparent clearance (CL/F) and volume of distribution (V/F) were 31 L/h and 422 L, respectively, with a typical terminal half-life of about 10 hours. H3B-6545 was absorbed fast, with a typical tmax of about 4 hours. A moderate to high variability (40-60%) was identified in major PK parameters (CL/F, V/F, bioavailability [F1]). A high-fat meal increased bioavailability by approximately 45% and prolonged tmax, roughly from 4 hours to 6 hours post dose. No significant effect was identified from other covariates: age, body weight, race, albumin, AST, ALP, ALT, bilirubin and creatinine clearance. CONCLUSIONS: H3B-6545 PK profiles in breast cancer patients were well described by a one-compartment disposition model with no significant effect of demographics, liver and renal function. When administered with a high fat meal, H3B-6545 exposure was modestly increased. Citation Format: Oneeb Majid, Jianjun Alan Xiao, Tarek Sahmoud, Sanae Yasuda, Lisa Cantagallo, Erika P Hamilton, Timothy Pluard, Dejan Juric, Antonio Gualberto, Ziad Husseiin. Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-15.

Purpose:To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missense HRAS mutations.Patients and Methods:A total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program including HRAS. Those with missense HRAS mutations or STK11:rs2075606 received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-day treatment cycles. The primary endpoint was progression-free survival at 6 months (PFS6).Results:We identified 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11:rs2075606 carriers. In 21 patients enrolled in the study, 14 and 7 patients had missense HRAS mutations and STK11:rs2075606, respectively. The most frequently observed adverse events included fatigue (86%) and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as an STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. The overall response rate by intent-to-treat analysis was 24% (4 missense and one nonsense frameshift HRAS mutation); no response was observed in patients with urothelial carcinoma with wild-type HRAS tumors. Five responses were observed in 12 evaluable patients of 15 with tumors carrying HRAS mutations.Conclusions:Oral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatment-refractory urothelial carcinoma containing HRAS mutations.

O objetivo deste estudo é investigar as relações entre a estrutura de capital e a rentabilidade das empresas listadas na B3 nos anos de 2011 a 2019. A partir de 1.940 observações, foram estimados três modelos econométricos por meio de regressões quantílicas e dados agrupados (POLS). Os resultados evidenciaram que o endividamento de curto prazo afeta positivamente a rentabilidade das empresas, com destaque para aquelas situadas no 1º quantil (menor rentabilidade) e 9º quantil (maior rentabilidade). Não foi identificado efeito estatisticamente significante dos endividamentos de longo prazo e total sobre a rentabilidade das empresas. Estes resultados contrariam a teoria da irrelevância da fonte de financiamento proposta por Modigliani e Miller (1958), entretanto, não é possível concluir que contrariam a proposição da teoria de Pecking Order, pois, não se examinou a existência de benefícios fiscais associados às escolhas de endividamento das empresas que compuseram a amostra. Ainda que inconclusiva para os efeitos do endividamento de longo prazo e total, esta pesquisa avança em relação aos estudos anteriores sobre esta temática ao aplicar um método de estimação ainda pouco explorado na literatura em Contabilidade e Finanças e que se mostrou aderente às características dos dados.

RESUMO: O presente estudo busca responder às seguintes questões: há evidências de inconsistência intertemporal em decisões que envolvem o recebimento de valores monetários? As pessoas estão sujeitas ao efeito magnitude em decisões intertemporais que envolvem o recebimento de valores monetários? O objetivo deste artigo é identificar inconsistências em decisões intertemporais que envolvam o recebimento de recursos monetários em diferentes momentos. Parte-se do pressuposto que decisões intertemporais que envolvem montantes em dinheiro podem ser igualmente afetadas pelo efeito magnitude. Este é um achado robusto na literatura, tendo sido identificado em escolhas hipotéticas que envolvem dinheiro. Para abordar a questão, procedeu-se o cálculo da taxa de desconto implícita dos indivíduos e, em seguida, classificaram-se os indivíduos segundo o construto "impaciência". Foram utilizados cenários adaptados de Sutter et al. (2013). Na análise dos dados, foi empregado um teste não paramétrico para diferença de médias e identificadas as características mais relevantes dos respondentes da survey. Há evidências de comportamento inconsistente nas decisões intertemporais para os cenários apresentados, com ocorrência de impaciência crescente para intervalos de tempo deslocados para o futuro. Tal achado vai de encontro à literatura empírica sobre desconto hiperbólico. Paralelamente, observou-se a ocorrência do efeito magnitude, ratificando achados anteriores sobre quantias monetárias aplicadas a escolhas inter-temporais de longo prazo. ABSTRACT: This study seeks to answer the following questions: Is there evidence of intertemporal inconsistency in the decisions that involve the reception of monetary values? Are people subject to the magnitude effect of intertemporal decisions that involve the reception of monetary values? In doing so, this research will try to identify inconsistencies in intertemporal choices involving the reception of monetary resources at different times, grounded in the premise that these type of decisions could also be affected by the so-called magnitude effect, a robust finding that has been identified for hypothetical choices involving money. To address this issue, we calculated the implicit discount rate of individuals and then classified these individuals based on the construct of "impatience." Adapted scenarios from the work by Sutter et al. (2013) were used for this research, whose data analysis phase involved non-parametric testing to differentiate medians and identify the most relevant characteristics of respondents. There is evidence of inconsistent behavior in intertemporal choices for the scenarios presented, with the occurrence of growing impatience for the intervals shifted into the future, a finding that goes against those of the empirical literature on hyperbolic discounting. In addition, the occurrence of the magnitude effect was proved, confirming previous research findings on monetary amounts applied to long-term intertemporal choices. RESUMEN: El estudio busca contestar a las siguientes cuestiones: ¿hay evidencias de inconsistencia intertemporal en decisiones que involucran la recepción de valores monetarios? ¿Están sujetas las personas al efecto magnitud en decisiones intertemporales que involucran la recepción de valores monetarios? El propósito del artículo es identificar inconsistencias en decisiones intertemporales que involucran la recepción de recursos monetarios en distintos momentos. Se parte de la premisa de que decisiones intertemporales que involucren montos en dinero pueden igualmente afectarse por el efecto magnitud. Este es un hallazgo robusto en la literatura, habiéndose identificado en escogencias hipotéticas que involucran dinero. Para abordar la cuestión, se realizó el cálculo de la tasa de descuento implícita de los individuos y, en seguida, se clasificaron los individuos según el constructo "impaciencia". Se utilizaron escenarios adaptados de Sutter et al. (2013). En el análisis de los datos, se empleó la prueba no paramétrica para diferenciar medianas e identificar las características más relevantes de los respondientes de la survey. Hay evidencias de conducta inconsistente en las decisiones intertemporales para los escenarios presentados, con ocurrencia de impaciente creciente para intervalos desplazados para el futuro. Tal hallazgo va en contra de la literatura empírica acerca del descuento hiperbólico. En paralelo, se observó la ocurrencia del efecto magnitud, ratificando hallazgos anteriores sobre montos monetarios aplicados a escogencias intertemporales de largo plazo. RÉSUMÉ: La présente étude cherche à répondre aux questions suivantes : existe-t-il des preuves d'incohérence intertemporelle dans les décisions impliquant la réception de valeurs monétaires ? Les gens sont-ils soumis à l'effet de magnitude dans les décisions intertemporelles impliquant la réception de valeurs monétaires ? Le but de cet article est d'identifier les incohérences dans les décisions intertemporelles qui impliquent la réception de ressources monétaires à des moments différents. On suppose que les décisions intertemporelles impliquant des sommes d'argent peuvent être également affectées par l'effet de magnitude. Il s'agit d'une constatation robuste dans la littérature, ayant été identifiée dans des choix hypothétiques impliquant de l'argent. Pour résoudre le problème, le taux d'actualisation implicite des individus a été calculé, puis les individus ont été classés selon le construit « impatience ». On a employé des scénarios adaptés de Sutter et al. (2013). Dans l'analyse des données, on a utilisé un test non paramétrique pour la différence des moyennes et on a identifié les caractéristiques les plus pertinentes des répondants à l'enquête. Il existe des preuves de comportement incohérent dans les décisions intertemporelles pour les scénarios présentés, avec une impatience croissante pour les intervalles de temps décalés vers le futur. Cette constatation est conforme à la littérature empirique sur l'actualisation hyperbolique. Dans le même temps, on a observé l'effet de magnitude, en confirmant les résultats antérieurs sur les montants monétaires appliqués aux choix intertemporels de long terme.

O presente estudo teve como objetivo primário, analisar os efeitos da utilização da Cisão como mecanismo de Reorganização Societária (RS) para a sustentação Estratégica de um Planejamento Tributário (PT) em uma empresa Baiana e, secundariamente buscou propor um modelo de PT diferente do convencional. Para tanto foi realizado um estudo documental e bibliográfico, complementado por um estudo de caso com abordagem exploratória e descritiva, buscando comparar, analisar e evidenciar os efeitos fiscais da RS na empresa em questão. Os achados revelam que a reorganização societária pode ser utilizada no planejamento tributário alinhada com os objetivos estratégicos do negócio de forma efetiva. Observa-se através da análise que, se a empresa em questão segregar o seu negócio através da Cisão Parcial em suas duas atividades, poderá optar por outro regime tributário em ambas o que reduzirá sua carga tributária quase pela metade e permitirá uma maximização dos lucros, aumentando assim a sustentabilidade financeira e a eficiência empresarial.

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-23T00:14:47Z No. of bitstreams: 1 8380-Texto do artigo-26294-1-10-20190606(1).pdf: 462961 bytes, checksum: 4f18be210908f05f5b1be8ce283eafe4 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-07-10T17:51:54Z (GMT) No. of bitstreams: 1 8380-Texto do artigo-26294-1-10-20190606(1).pdf: 462961 bytes, checksum: 4f18be210908f05f5b1be8ce283eafe4 (MD5) Made available in DSpace on 2021-07-10T17:51:54Z (GMT). No. of bitstreams: 1 8380-Texto do artigo-26294-1-10-20190606(1).pdf: 462961 bytes, checksum: 4f18be210908f05f5b1be8ce283eafe4 (MD5) Previous issue date: 2019-06-01 Buscou-se verificar o efeito do endividamento por emissão de debêntures sobre os múltiplos das empresas emissoras, e dentre os múltiplos possivelmente afetados, qual apresentou maior nível de sensibilidade a tais efeitos. Para tanto, foram observadas as empresas de capital aberto, com informações disponíveis na Comissão de Valores Mobiliários (CVM) que emitiram debêntures no período entre 2010 a 2017. A literatura sobre estrutura de capital aborda a teoria de pecking order, a teoria de trade-off e a teoria de agência e aspectos relacionados ao endividamento por emissão de títulos de dívida, precificação de ações e avaliação por múltiplos. Os procedimentos metodológicos envolveram a aplicação de método quantitativos, de forma mais específica, análise descritiva e teste não-paramétrico de Wilcoxon. A amostra foi composta por cinquenta e oito empresas. Os resultados sugerem que o endividamento por emissão de debêntures ocasiona uma redução contínua nas dos múltiplos observados e que o múltiplo Preço/Vendas possui maior nível de sensibilidade à emissão de debêntures. As conclusões obtidas neste estudo, são condizentes com conclusões obtidas por Coelho (2008), que identificou efeito nulo ou negativo a emissão de debêntures sobre o preço das ações. Rio Grande - RS

Background Real-world data (RWD) has been increasingly used in drug development. A reliable evaluation of efficacy for current treatments is challenging with very limited publication data of clinical trials available. The RWD provides a unique value and an alternative way to achieve such goal. Use data from metastatic Breast Cancer (mBC) patients in the real world clinical practice, we examine the treatment patterns and durations of different endocrine monotherapies in various clinical settings. Methods We obtained Flatiron Health subject-level mBC data set which consists a group of 20645 mBC patients. The analysis set consisted of subjects who were ER+/Her2-/(PgR+ or PgR-), received at least one prior line of CDK4/6 inhibitor (mono or combo) and one prior line of endocrine therapy (mono or combo) in the mBC settings, and had an ECOG performance score Result Out of all subjects in the mBC RWD database, 263 subjects met the inclusion criteria and were included in the analysis set. Among all 263 ER+/Her2- subjects, the median TTD of endocrine monotherapies was 3.0 months (95% CI: 2.8-3.7 months, N=263) in all subjects, 3.7 months (95% CI: 3.0-4.3 months, N=186) in PgR+ group and 2.1 months (95% CI: 1.9-2.9 months, N=77) in PgR- group. Among 186 ER+/PgR+/Her2- subjects, 1) the median TTD of endocrine monotherapies was 3.3 months (95% CI: 2.8-4.6 months, N=153) in ECOG=3 prior treatment lines group. Conclusion By investigating the RWD, we observed that the PgR status is prognostic in post CDK setting: endocrine monotherapies in PgR+ group has longer TTD compared to PgR- group in ER+/Her2- mBC subjects. By further looking into ER+/PgR+/Her2- subjects, we observed different treatment durations of endocrine therapies in various clinical scenarios, which may provide a helpful understanding of the mBC monotherapy treatments. Citation Format: Tenghui Chen, Zhaojie Zhang, Lei Gao, Catherine Scholz, Antonio Gualberto, Lihua Yu, Kun Yu. Using real-world data to evaluate the performance of endocrine therapies in ER+/Her2- metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5247.

Mutations in theWe enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for mOf the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-18T17:33:23Z No. of bitstreams: 1 5355-Texto do Artigo-23902-1-10-20210301.pdf: 413738 bytes, checksum: c5c3afc351f2abe36f84a3a674c7dfe8 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-06-21T19:22:38Z (GMT) No. of bitstreams: 1 5355-Texto do Artigo-23902-1-10-20210301.pdf: 413738 bytes, checksum: c5c3afc351f2abe36f84a3a674c7dfe8 (MD5) Made available in DSpace on 2021-06-21T19:22:38Z (GMT). No. of bitstreams: 1 5355-Texto do Artigo-23902-1-10-20210301.pdf: 413738 bytes, checksum: c5c3afc351f2abe36f84a3a674c7dfe8 (MD5) Previous issue date: 2021-03-01 Ministério da Ciência, Tecnologia, Inovações e Comunicações (MCTIC) O presente estudo realizou uma revisão sistemática da produção acadêmica acerca do Exame Nacional de Desempenho de Estudantes na área de Contabilidade e, para tanto, explorou os seguintes objetivos específicos: (i) escanear os periódicos nacionais com maior classificação no Qualis – CAPES; (ii) analisar quantitativa e qualitativamente os artigos localizados, incluindo a verificação de indicadores bibliométricos propostos na literatura; (iii) sintetizar graficamente a evolução da produção sobre esse tópico no período. O método de análise foi descritivo e bibliométrico, abarcando mais de dez anos de produção acadêmica sobre o ENADE em periódicos nacionais, além de teses de doutorado em Ciências Contábeis. Identificou-se um crescimento da produção sobre o ENADE nos últimos anos. Os achados referentes a indicadores bibliométricos específicos mostram que as Leis de Lotka, Bradford e Zipf são ratificadas. Ao final, é apresentado um quadro geral da produção acadêmica sobre o ENADE em mais de uma década, fornecendo indicativos de tendência para a pesquisa na área. Chapecó

Key Points Gene expression and mutational analysis confirm the differences among the 3 peripheral TCL subclasses: AITL, PTCL-NOS, and PTCL-TFH.The expression of a gene set, including B-cell genes, is an IPI-independent prognostic factor for AITL cases., Visual Abstract, Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-22T23:21:06Z No. of bitstreams: 1 2020_CFF443.pdf: 972393 bytes, checksum: 8cde816e8597cc3ed0d81d4415bfc9fc (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-06-30T17:36:27Z (GMT) No. of bitstreams: 1 2020_CFF443.pdf: 972393 bytes, checksum: 8cde816e8597cc3ed0d81d4415bfc9fc (MD5) Made available in DSpace on 2021-06-30T17:36:27Z (GMT). No. of bitstreams: 1 2020_CFF443.pdf: 972393 bytes, checksum: 8cde816e8597cc3ed0d81d4415bfc9fc (MD5) Previous issue date: 2020-12-15 Com suporte na Teoria dos Contratos e na Teoria Positiva da Contabilidade, este trabalho investiga a relação entre força de trabalho e gerenciamento de resultados nas empresas brasileiras. Em que pese a relação entre força de trabalho e gerenciamento de resultados tenha sido objeto de importantes pesquisas internacionais desde a década de 80, sobretudo nos Estados Unidos, permanece, em âmbito nacional, uma carência de estudos com esse objeto. Cabe destacar, ainda, que os modelos sindicais do Brasil e dos Estados Unidos, onde foi realizada a maioria das pesquisas, são diferentes, o que agrega relevância ao estudo. Foram analisadas 119 empresas brasileiras ativas na B3, durante o período de 2012 a 2018, através de dados em painel por efeitos fixos. O modelo de Dechow et al. (2012) foi utilizado para detectar o gerenciamento de resultados por accruals. Para capturar a intensidade da força do trabalho, foi proposta uma nova proxy, baseada na Demonstração de Valor Adicionado, além das proxies apresentadas por Hilary (2006). Os resultados obtidos com base na proxy proposta nesta pesquisa evidenciam que a força de trabalho influencia na prática de gerenciamento de resultados por accruals. Tais achados contribuem para a linha de pesquisa que verifica a interferência da força de trabalho sobre o gerenciamento de resultados, enriquecendo a literatura internacional, tendo em vista que o modelo sindical brasileiro é diferente do norte-americano, onde foi realizada a maioria das pesquisas. Além disso, contribui para as pesquisas nacionais sobre gerenciamento de resultados, haja vista a identificação de um novo determinante potencial para esta prática. Foz do Iguaçu

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-19T21:00:22Z No. of bitstreams: 1 admin_pdf_2020_EnANPAD_FIN297(1).pdf: 385347 bytes, checksum: 475535b70e985230c701d2c0fa597a67 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-06-30T17:21:05Z (GMT) No. of bitstreams: 1 admin_pdf_2020_EnANPAD_FIN297(1).pdf: 385347 bytes, checksum: 475535b70e985230c701d2c0fa597a67 (MD5) Made available in DSpace on 2021-06-30T17:21:05Z (GMT). No. of bitstreams: 1 admin_pdf_2020_EnANPAD_FIN297(1).pdf: 385347 bytes, checksum: 475535b70e985230c701d2c0fa597a67 (MD5) Previous issue date: 2020-10-14 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) e Fundação de Amparo à Pesquisa da Bahia (Fapesb). O objetivo deste estudo é investigar as relações entre a estrutura de capital e a rentabilidade das empresas listadas na B3 nos anos de 2011 a 2019. A partir de 1.940 observações, foram estimados três modelos econométricos por meio de regressões quantílicas e dados agrupados (POLS). Os resultados evidenciaram que o endividamento de curto prazo afeta positivamente a rentabilidade das empresas, com destaque para aquelas situadas no 1º quantil (menor rentabilidade) e 9º quantil (maior rentabilidade). Não foi identificado efeito estatisticamente significante dos endividamentos de longo prazo e total sobre a rentabilidade das empresas. Estes resultados contrariam a teoria da irrelevância da fonte de financiamento proposta por Modigliani e Miller (1958), entretanto, não é possível concluir que contrariam a proposição da teoria de Pecking Order, pois, não se examinou a existência de benefícios fiscais associados às escolhas de endividamento das empresas que compuseram a amostra. Ainda que inconclusiva para os efeitos do endividamento de longo prazo e total, esta pesquisa avança em relação aos estudos anteriores sobre esta temática ao aplicar um método de estimação ainda pouco explorado na literatura em contabilidade e finanças e que se mostrou aderente às características dos dados. versão online

Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of HRAS-mutant and wild-type head and neck squamous cell carcinoma (HNSCC) xenograft models. Tipifarnib treatment displaced both mutant and wild-type HRAS from membranes but only inhibited proliferation, survival, and spheroid formation of HRAS-mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRAS-mutant xenografts tested but displayed no activity in six HRAS wild-type patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, induction of apoptosis, and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FTase inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDXs. These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.

BackgroundTo the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC.MethodsThe current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22months (range, 6-55months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.ResultsA total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9months (range, 3-14months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7months (95% confidence interval, 5.9-10.1months), and the median overall survival was 18months (95% confidence interval, 9.6-22.4months) with approximately 58.6% of patients alive at 1year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.ConclusionsTipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6months.

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-19T20:37:37Z No. of bitstreams: 1 10-1108_REGE-07-2019-0077.pdf: 297128 bytes, checksum: 603d42abfe485c3055802ed6c3c41d12 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-07-24T19:01:40Z (GMT) No. of bitstreams: 1 10-1108_REGE-07-2019-0077.pdf: 297128 bytes, checksum: 603d42abfe485c3055802ed6c3c41d12 (MD5) Made available in DSpace on 2021-07-24T19:01:40Z (GMT). No. of bitstreams: 1 10-1108_REGE-07-2019-0077.pdf: 297128 bytes, checksum: 603d42abfe485c3055802ed6c3c41d12 (MD5) Previous issue date: 2020-06-03 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) The purpose of this study is to identify arrangements of fully funded defined contribution (FF-DC)pension plans associated with the continuity of retirement savings. Design/methodology/approach – The authors adopted an experimental design composed of a control group and two treatment groups. In all groups, individuals made decisions throughout nine periods: five during the working period and four at the postretirement stage. The authors asked participants if they wanted to join a pension plan, and which plan. The authors offered three plans with different risk profiles: plan 1 (high risk), plan 2 (moderate) and plan 3 (low risk) and one risk-free plan, plan 4. In treatment groups 1 and 2, there was an automatic enrollment of the participants in the default plan (moderate risk), and in the following periods they had to decide whether to continue contributing, and in this case, to which plan, with a defined percentage. Findings – In treatment scenarios, participants chose the riskiest plan in all periods of the experiment, and most of them chose the risk-free plan in period 5. These findings suggest that pension plans with automatic enrollment, employer matching and low risk foster the continuation of retirement savings. Research limitations/implications – The research has as limitation the fact that the sample is not representative of the population and therefore does not allow generalizations. This is because the authors use social media ads to prospect respondents. Practical implications – The research’s findings can be relevant for the design of public policies for private pension plans, suggesting that compulsory automatic enrollment can be used as default in plans offered by the employers. The results encourage the inclusion of behavioral elements in the design of the pension system, paying attention to the nudges. In this sense, it is possible to increase participation in the pension plan and develop low cost programs to increase the amount accumulated by people before retirement. Social implications – Decision-making architecture, such as automatic enrollment,can improve individuals’ retirement decisions, affecting savings and welfare in the long run. Originality/value – Although the effect of pension plan designs is widely studied in other countries, such as the United States and United Kingdom, the authors are unaware of a national empirical research that seeks to understand how different arrangements affect an individual choice through an experiment. São Paulo

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-19T21:15:46Z No. of bitstreams: 1 32659-131691-1-PB.pdf: 644208 bytes, checksum: 49b0540beb2f9fa9513d35357196b2c6 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-07-10T15:50:26Z (GMT) No. of bitstreams: 1 32659-131691-1-PB.pdf: 644208 bytes, checksum: 49b0540beb2f9fa9513d35357196b2c6 (MD5) Made available in DSpace on 2021-07-10T15:50:26Z (GMT). No. of bitstreams: 1 32659-131691-1-PB.pdf: 644208 bytes, checksum: 49b0540beb2f9fa9513d35357196b2c6 (MD5) Previous issue date: 2020-05-01 A presente pesquisa buscou verificar a influência do recordkeeping sobre a confiança e reciprocidade, analisando o efeito moderador da cultura individualista versus coletivista de estudantes de graduação de ciências contábeis. Utilizou-se o questionário “Values Survey Module 1994”, desenvolvido por Hofstede (1990) para captar a dimensão cultural individualista versus coletivista. Para avaliar a confiança e a reciprocidade foi utilizado o modelo experimental de Basu et al. (2009), através da aplicação do trust game. No desenho do jogo existiam participantes ocupando o papel de investidor e participantes ocupando o papel de administrador como ilustração de uma transação entre agentes estranhos. O grupo de tratamento foi aquele cujo cenário compreendia um ambiente econômico onde os jogadores tinham a opção de manter registros (recordkeeping) e, como grupo de controle, o cenário em que os participantes não tiveram acesso ao recordkeeping. Para testar as hipóteses comportamentais foram aplicadas regressões com dados em painel de efeito aleatórios estimado pelos mínimos quadrados generalizados (GLS). Os resultados indicaram que os investidores mais individualistas/menos coletivistas aumentaram o nível de confiança, enquanto não foi possível identificar a influência da contabilidade no nível de reciprocidade dos agentes. Notou-se também que o aumento da confiança e reciprocidade está relacionado com sujeitos com idade menor. Entre as limitações da pesquisa é possível citar que os achados não podem ser generalizados para o conjunto da população e que, embora haja uma simulação envolvendo vários períodos, não há um acompanhamento longitudinal dos indivíduos. Salvador

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-19T21:15:46Z No. of bitstreams: 1 32659-131691-1-PB.pdf: 644208 bytes, checksum: 49b0540beb2f9fa9513d35357196b2c6 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-07-10T15:50:26Z (GMT) No. of bitstreams: 1 32659-131691-1-PB.pdf: 644208 bytes, checksum: 49b0540beb2f9fa9513d35357196b2c6 (MD5) Made available in DSpace on 2021-07-10T15:50:26Z (GMT). No. of bitstreams: 1 32659-131691-1-PB.pdf: 644208 bytes, checksum: 49b0540beb2f9fa9513d35357196b2c6 (MD5) Previous issue date: 2020-05-01 A presente pesquisa buscou verificar a influência do recordkeeping sobre a confiança e reciprocidade, analisando o efeito moderador da cultura individualista versus coletivista de estudantes de graduação de ciências contábeis. Utilizou-se o questionário “Values Survey Module 1994”, desenvolvido por Hofstede (1990) para captar a dimensão cultural individualista versus coletivista. Para avaliar a confiança e a reciprocidade foi utilizado o modelo experimental de Basu et al. (2009), através da aplicação do trust game. No desenho do jogo existiam participantes ocupando o papel de investidor e participantes ocupando o papel de administrador como ilustração de uma transação entre agentes estranhos. O grupo de tratamento foi aquele cujo cenário compreendia um ambiente econômico onde os jogadores tinham a opção de manter registros (recordkeeping) e, como grupo de controle, o cenário em que os participantes não tiveram acesso ao recordkeeping. Para testar as hipóteses comportamentais foram aplicadas regressões com dados em painel de efeito aleatórios estimado pelos mínimos quadrados generalizados (GLS). Os resultados indicaram que os investidores mais individualistas/menos coletivistas aumentaram o nível de confiança, enquanto não foi possível identificar a influência da contabilidade no nível de reciprocidade dos agentes. Notou-se também que o aumento da confiança e reciprocidade está relacionado com sujeitos com idade menor. Entre as limitações da pesquisa é possível citar que os achados não podem ser generalizados para o conjunto da população e que, embora haja uma simulação envolvendo vários períodos, não há um acompanhamento longitudinal dos indivíduos. Salvador

Submitted by Antonio Gualberto Pereira (antoniopereira@ufba.br) on 2021-06-19T21:29:40Z No. of bitstreams: 1 2024-7232-1-PB.pdf: 371062 bytes, checksum: 119ff523314e0cba230f23e4ac299318 (MD5) Approved for entry into archive by Marivalda Araujo (masilva@ufba.br) on 2021-07-10T14:07:54Z (GMT) No. of bitstreams: 1 2024-7232-1-PB.pdf: 371062 bytes, checksum: 119ff523314e0cba230f23e4ac299318 (MD5) Made available in DSpace on 2021-07-10T14:07:55Z (GMT). No. of bitstreams: 1 2024-7232-1-PB.pdf: 371062 bytes, checksum: 119ff523314e0cba230f23e4ac299318 (MD5) Previous issue date: 2020-04-20 No meio acadêmico, o Mercado de Capitais tornou-se um laboratório de testes, onde pesquisadores buscam verificar por meio de análises estatísticas se determinada informação contábil é ou não relevante para o mercado. Por meio disto, alguns estudos buscaram analisar qual viria ser a melhor estimativa para prever futuros fluxos de caixa gerados pela empresa, visto que, os preços das ações são estimados como iguais ao valor presente dos fluxos de caixa futuros. No entanto, para a avaliação da situação econômico-financeira de uma empresa, têm-se duas principais informações contábeis, o Lucro Líquido (regime de competência) e o Fluxo de Caixa (regime de caixa) gerado. Diante disto, o objetivo da pesquisa é analisar de forma comparativa a capacidade preditiva do Fluxo de Caixa Operacional e do Lucro Líquido do exercício na previsão de futuros fluxos de caixa de empresas listadas na bolsa. A metodologia de pesquisa baseou-se em estudos como o de Habbib (2010) e Agana (2016) e utilizou dados financeiros coletados na Brasil, Bolsa, Balcão- B3, do período compreendido de 2012 a 2016. Foram utilizadas técnicas quantitativas para analisar a acurácia preditiva das variáveis, além das regressões lineares foi adotado o U de Theil para melhor comparação. Os resultados sugerem que o Lucro Líquido possui maior poder preditivo para estimar futuros Fluxos de Caixa Operacional, corroborando com estudos como os de Chong, (2012), Takhtae e Karimi (2013) e Agana (2016). Monte Carmelo - Minas Gerais

To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missenseA total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program includingWe identified 16 (7%) missenseOral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatment-refractory urothelial carcinoma containing

Portuguese abstract: Frente a lacuna por que passa a teoria contabil que nao conta com um corpo de conhecimentos consolidado, discutir alguns delineamentos significativos para pesquisa e uma forma de fomentar um entendimento mais loquaz do atual estado da arte neste campo do conhecimento e apontar caminhos frente aos desafios que se apresentam. O objetivo deste trabalho e indicar alguns aspectos relevantes definidos pela teoria positiva da contabilidade, a despeito da teoria dos contratos e seus desdobramentos para o papel da contabilidade na minimizacao dos conflitos de agencia e reducao da assimetria de informacao, o papel da governanca corporativa quanto a melhoria dos controles internos e busca de uma maior transparencia nas relacoes entre agente e principal e, nao menos importante, o papel da auditoria no monitoramento dos contratos. A teoria da contabilidade tem se servido deste cabedal teorico-conceitual para explicar muito dos fenomenos sobre os quais “lanca luz” e, frente as novas demandas apontadas pelo processo de regulamentacao por que passa a contabilidade, haja vista a propria Lei Sarbanes & Oxley, representa um pilar a ser observado cuidadosamente no estudo das diversas nuances deste cenario desafiador e instigante. English abstract: Faced with the gap that the accounting theory goes through, which does not have a consolidated body of knowledge, discussing some significant designs for research is a way to foster a more loquacious understanding of the current state of the art in this field of knowledge and to point out ways in the face of the challenges that they introduce themselves. The objective of this work is to indicate some relevant aspects defined by the positive theory of accounting, in spite of the theory of contracts and its consequences for the role of accounting in minimizing agency conflicts and reducing information asymmetry, the role of corporate governance regarding improvement of internal controls and search for greater transparency in the relationship between agent and principal and, not least, the role of auditing in monitoring contracts. Accounting theory has used this theoretical-conceptual framework to explain much of the phenomena on which it “sheds light” and, in view of the new demands pointed out by the regulatory process that accounting goes through, given the Sarbanes & Oxley Act itself, it represents a pillar to be carefully observed in the study of the diverse nuances of this challenging and exciting scenario.

Patients diagnosed with T-cell leukemias and T-cell lymphomas (TCLs) still have a poor prognosis and an inadequate response to current therapies, highlighting the need for targeted treatments. We have analyzed the potential therapeutic value of the farnesyltransferase inhibitor, tipifarnib, in 25 TCL cell lines through the identification of genomic and/or immunohistochemical markers of tipifarnib sensitivity. More than half of the cell lines (60%) were considered to be sensitive. Tipifarnib reduced cell viability in these T-cell leukemia and TCL cell lines, induced apoptosis and modified the cell cycle. A mutational study showed TP53, NOTCH1 and DNMT3 to be mutated in 84.6%, 69.2% and 30.0% of sensitive cell lines, and in 62.5%, 0% and 0% of resistant cell lines, respectively. An immunohistochemistry study showed that p-ERK and RelB were associated as potential biomarkers of tipifarnib sensitivity and resistance, respectively. Data from RNA-seq show that tipifarnib at IC50 after 72 h downregulated a great variety of pathways, including those controlling cell cycle, metabolism, and ribosomal and mitochondrial activity. This study establishes tipifarnib as a potential therapeutic option in T-cell leukemia and TCL. The mutational state of NOTCH1, p-ERK and RelB could serve as potential biomarkers of tipifarnib sensitivity and resistance. Acknowledgements: We thank Phil Mason for his help in correcting the English and Helena Pisonero (IDIVAL) for technical assistance in the lab. The research was supported by grants from the Instituto de Salud Carlos III, from the Ministerio de Economía, Industria y Competitividad [SAF2013-47416-R, CIBERONC-ISCIII, ISCIII-MINECO-AES-FEDER (Plan Estatal I + D + I 2013–2016)}. The AECC PROYE18054PIRI, CAM B2017/BMD-3778, PIC97/2017_FJD, PIE15/0081 and PIE16/01294; Asociación Española Contra el Cáncer (AECC), Comunidad Autónoma de Madrid and Instituto Formación e Investigación, Hospital Universitario Marqués de Valdecilla (IDIVAL): NVAL16/18. A E-C is funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER.