RESUMEN

Objective.Recently, a new and promising approach for range verification was proposed. This method requires the use of two different ion species. Due to their equal magnetic rigidity, fully ionized carbon and helium ions can be simultaneously accelerated in accelerators like synchrotrons. At sufficiently high treatment energies, helium ions can exit the patient distally, reaching approximately three times the range of carbon ions at an equal energy per nucleon. Therefore, the proposal involves adding a small helium fluence to the carbon ion beam and utilizing helium as an online range probe during radiation therapy. This work aims to develop a software framework for treatment planning and motion verification in range-guided radiation therapy using mixed carbon-helium beams.Approach.The developed framework is based on the open-source treatment planning toolkit matRad. Dose distributions and helium radiographs were simulated using the open-source Monte Carlo package TOPAS. Beam delivery system parameters were obtained from the Heidelberg Ion Therapy Center, and imaging detectors along with reconstruction were facilitated by ProtonVDA. Methods for reconstructing the most likely patient positioning error scenarios and the motion phase of 4DCT are presented for prostate and lung cancer sites.Main results.The developed framework provides the capability to calculate and optimize treatment plans for mixed carbon-helium ion therapy. It can simulate the treatment process and generate helium radiographs for simulated patient geometry, including small beam views. Furthermore, motion reconstruction based on these radiographs seems possible with preliminary validation.Significance.The developed framework can be applied for further experimental work with the promising mixed carbon-helium ion implementation of range-guided radiotherapy. It offers opportunities for adaptation in particle therapy, improving dose accumulation, and enabling patient anatomy reconstruction during radiotherapy.

Asunto(s)

Carbono , Helio , Planificación de la Radioterapia Asistida por Computador , Helio/uso terapéutico , Planificación de la Radioterapia Asistida por Computador/métodos , Humanos , Carbono/uso terapéutico , Neoplasias de la Próstata/radioterapia , Masculino , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/diagnóstico por imagen , Dosificación Radioterapéutica , Método de Montecarlo , Radioterapia de Iones Pesados/métodos

RESUMEN

OBJECTIVE: To identify sociodemographic and behavioral factors associated with abdominal obesity (AO) and high body fat percentage (high BF%) in adolescents from the city of Curitiba-PR. METHODS: The sample consisted of 1,732 adolescents, aged 11 to 19 years, of both genders. The triceps and calf skinfolds were measured for the calculation of BF%, as well as the waist circumference. A questionnaire was completed by adolescents with the following type of residence, socioeconomic status, time spent watching TV on weekdays and weekends, and daily energy expenditure. Logistic regression was used to measure the association of sociodemographic and behavioral variables with abdominal obesity and high BF%. RESULTS: Female were more likely to have high BF% (OR: 2.73; 95% CI: 2.32-3.33), but were less likely to have abdominal obesity (OR: 0.58; 95% CI: 0.44-0.78). Older individuals (16-19 have high BF% (OR: 1.36; 95% CI: 1.02-1.83). The older age groups (13-15 years and 16-19 years) had an inverse association with abdominal obesity. Regarding daily energy expenditure, the less active individuals were more likely to present high BF% (OR: 1.36; 95% CI: 1.07-1.71) and obesity (OR: 1.40; 95% CI: 1.09-1.80). CONCLUSIONS: Interventions to increase physical activity levels in young people should be designed in order to combat excess body fat should designed to combat excess adiposity.

Asunto(s)

Adiposidad , Conducta del Adolescente , Obesidad Abdominal/epidemiología , Obesidad Infantil/epidemiología , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Factores Socioeconómicos , Adulto Joven

RESUMEN

Objetivo: Identificar fatores sociodemográficos e comportamentais associados à obesidade abdominal (OA) e ao percentual de gordura corporal elevado (%GC elevado) em adolescentes de Curitiba-PR. Métodos: A amostra probabilística foi composta por 1.732 adolescentes, de 11 a 19 anos, de ambos os sexos, da rede pública de ensino. Foram coletadas as medidas de dobras cutâneas tricipital e panturrilha para o cálculo do %GC, além da medida da circunferência da cintura. Um questionário foi preenchido pelos adolescentes para avaliação das seguintes variáveis: sexo, idade, tipo de residência, nível socioeconômico, tempo gasto assistindo à TV durante a semana e o fim de semana, além do gasto energético diário. A regressão logística foi utilizada como medida de associação dos fatores sociodemográficos e comportamentais com a obesidade abdominal e o percentual de gordura corporal elevado. Resultados: As meninas apresentaram maior chance de ter o %GC elevado (OR: 2,73; IC95%: 2,32-3,33). Em contrapartida, têm menor chance de ter obesidade abdominal (OR: 0,58; IC95%: 0,44-0,78). Indivíduos mais velhos (16-19 anos) apresentaram maior chance de ter o %GC elevado (OR: 1,36; IC95%: 1,02-1,83). Em contrapartida, as faixas etárias mais elevadas (13-15 anos e 16-19 anos) tiveram uma associação inversa com a obesidade abdominal. Em relação ao gasto energético diário, os indivíduos menos ativos apresentaram maior chance de ter %GC elevado (OR: 1,36; IC95%: 1,07-1,71) e obesidade abdominal (OR: 1,40; IC95%: 1,09-1,80). Conclusões: Intervenções relacionadas ao aumento nos níveis de atividade física na população jovem devem ser elaboradas para o combate do excesso de adiposidade corporal. .

---

Objective: To identify sociodemographic and behavioral factors associated with abdominal obesity (AO) and high body fat percentage (high BF%) in adolescents from the city of Curitiba-PR. Methods: The sample consisted of 1,732 adolescents, aged 11 to 19 years, of both genders. The triceps and calf skinfolds were measured for the calculation of BF%, as well as the waist circumference. A questionnaire was completed by adolescents with the following type of residence, socioeconomic status, time spent watching TV on weekdays and weekends, and daily energy expenditure. Logistic regression was used to measure the association of sociodemographic and behavioral variables with abdominal obesity and high BF%. Results: Female were more likely to have high BF% (OR: 2.73; 95% CI: 2.32-3.33), but were less likely to have abdominal obesity (OR: 0.58; 95% CI: 0.44-0.78). Older individuals (1619 have high BF% (OR: 1.36; 95% CI: 1.02-1.83). The older age groups (13-15 years and 16-19 years) had an inverse association with abdominal obesity. Regarding daily energy expenditure, the less active individuals were more likely to present high BF% (OR: 1.36; 95% CI: 1.07-1.71) and obesity (OR: 1.40; 95% CI: 1.09-1.80). Conclusions: Interventions to increase physical activity levels in young people should be designed in order to combat excess body fat should designed to combat excess adiposity. .

Asunto(s)

Humanos , Masculino , Femenino , Adolescente , Adiposidad , Conducta del Adolescente , Obesidad Abdominal/epidemiología , Salud del Adolescente

RESUMEN

OBJECTIVES: SNCG in breast cancer is a marker for advanced and aggressive disease thereby correlating with a poor prognosis in patients. We set out to determine if SNCG expression in UPSC correlates with aggressive cellular properties, poor prognosis, and chemoresistance, and if silencing SNCG can reverse these attributes in vitro. METHODS: A focused, real time PCR array was performed comparing a papillary serous (SPEC2) and an endometrioid (Ishikawa) endometrial cancer cell line. SNCG was the most differentially expressed gene. SNCG expression was confirmed by real time PCR, Western blot, and immunohistochemistry (IHC) and correlated with outcomes in a pilot set of 20 UPSC patients. A stably transfected SPEC2 cell line was created using shSNCG oligonucleotides. The effect of SNCG knockdown in SPEC2 cells on cell proliferation and sensitivity to paclitaxel-induced apoptosis was measured using a cell viability assay, BrdU incorporation assay, as well as cleaved PARP analyses. RESULTS: SNCG mRNA as well as protein was highly expressed in SPEC2 cells while minimally to undetectable in several endometrioid endometrial cancer and normal endometrial cell lines. IHC also confirmed unique SNCG expression in UPSC tumors compared to low grade endometrial cancers. In UPSC patients, SNCG expression by IHC correlated with advanced stage and decreased progression-free survival. Knockdown of SNCG in SPEC2 cells caused a significant decrease in cell proliferation and increased sensitivity to paclitaxel-induced apoptosis. CONCLUSIONS: SNCG is a novel biomarker for aggressive disease and chemoresistance in UPSC and merits further investigation both as a prognostic tool and as a therapeutic target.

Asunto(s)

Biomarcadores de Tumor/biosíntesis , Carcinoma Papilar/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Proteínas de Neoplasias/biosíntesis , Neoplasias Uterinas/metabolismo , gamma-Sinucleína/biosíntesis , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Biomarcadores de Tumor/genética , Carcinoma Papilar/tratamiento farmacológico , Carcinoma Papilar/genética , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Paclitaxel/farmacología , ARN Interferente Pequeño/genética , Transfección , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , gamma-Sinucleína/antagonistas & inhibidores , gamma-Sinucleína/genética

RESUMEN

CONTEXT: Progesterone has been associated with promoting growth of uterine leiomyomas. The mechanisms involved remain unclear. OBJECTIVE: In this study we investigated the activation of the AKT pathway and its downstream effectors, glycogen synthase kinase-3b and Forkhead box O (FOXO)-1 by progesterone as a mechanism of proliferation and survival of leiomyoma cells. Inhibitors of the AKT pathway were used to demonstrate the role of phosphatidylinositol 3-kinase, AKT, and FOXO1 in contributing to cell proliferation and apoptosis. RESULTS: Treatment of leiomyoma cells with R5020 over a period of 72 h resulted in higher cell numbers compared with untreated cells. When cells were treated with 100 nm R5020 for 1 and 24 h, the levels of phospho(Ser 473)-AKT increased. This increase was inhibited when cells were cotreated with RU486. Treatment of leiomyoma cells with a phosphatidylinositol 3-kinase inhibitor, LY294 dramatically decreased levels of phospho(Ser 473)-AKT, despite R5020 treatment. In addition to increased phospho(Ser 473)-AKT levels, R5020 treatment resulted in an increase in phospho(Ser 256)-FOXO1 and phosphoglycogen synthase kinase-3b. Inhibition of AKT using API-59 decreased proliferation and cell viability even in the presence of R5020. Higher concentrations of API-59-induced apoptosis of leiomyoma cells, even in the presence of R5020. Psammaplysene A increased nuclear FOXO1 levels and did not affect cell proliferation but induced apoptosis of leiomyoma cells. CONCLUSIONS: The progestin, R5020, can rapidly activate the AKT pathway. Inhibition of the AKT pathway inhibits cell proliferation and promotes apoptosis of leiomyoma cells.

Asunto(s)

Leiomioma/patología , Proteína Oncogénica v-akt/fisiología , Progestinas/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias Uterinas/patología , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Técnica del Anticuerpo Fluorescente , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Humanos , Mifepristona/farmacología , Proteína Oncogénica v-akt/metabolismo , Fosforilación , Promegestona/farmacología

RESUMEN

OBJECTIVE: Endometrial cancer is the most common type of gynecologic cancer in the United States. In this study, we propose that a marine sponge compound, psammaplysene A (PsA) induces apoptosis in endometrial cancer cells through forced nuclear expression of FOXO1. METHODS: Ishikawa and ECC1 cells were treated with varying doses of PsA. FOXO1 protein localization was observed using immunofluorescent staining of cells. The effects of PsA on cell viability and proliferation were assessed using a cell viability assay and a BrdU incorporation assay respectively. Cell cycle analysis was performed using flow cytometry. To assess the role of FOXO1 in PsA-induced apoptosis, FOXO1 was silenced in ECC1 cells using siRNA technique, and overexpressed in Ishikawa cells using an adenovirus containing FOXO1 cDNAs. Western blots were used to measure levels of FOXO1 and cleaved PARP proteins. RESULTS: Treatment of both ECC1 and Ishikawa cells with PsA caused an increase in nuclear FOXO1 protein, a dramatic decrease in cell viability of approximately 5-fold (p<0.05) and minimal effect on proliferation. Furthermore, treatment of cells with PsA doubled the percentage of cells in the G2/M phase (p<0.05). PsA induced apoptosis in endometrial cancer cells. When FOXO1 was silenced in ECC1 cells and treated with PsA, the incidence of apoptosis decreased. In addition, overexpression of FOXO1 with PsA treatment increased apoptosis. CONCLUSIONS: Increasing nuclear FOXO1 function is important for the induction of apoptosis of endometrial cancer cells by PsA.

Asunto(s)

Apoptosis/efectos de los fármacos , Neoplasias Endometriales/tratamiento farmacológico , Factores de Transcripción Forkhead/biosíntesis , Tirosina/análogos & derivados , División Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/metabolismo , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Fase G2/efectos de los fármacos , Humanos , ARN Interferente Pequeño/genética , Transfección , Tirosina/farmacología

RESUMEN

OBJECTIVE: Endometrial cancer is the most common type of gynecologic cancer in the United States. In this study, we propose that inhibition of the AKT pathway sensitizes cells to chemotherapeutic agents by increasing FOXO1 expression. METHODS: Ishikawa and RL95 cells were treated with the AKT inhibitor (API-59CJ-OMe) alone and in combination with carboplatin or paclitaxel. Cells were counted using a hemocytometer and cell cycle analysis done with flow cytometry. Apoptosis was measured with TUNEL and Annexin V/DAPI staining. FOXO1 protein expression and localization was done using immunofluorescent staining of cells. Finally, the adenovirus containing triple mutant FOXO1 was used to overexpress the constitutively active FOXO1 in Ishikawa cells and its effects on cell viability were studied. RESULTS: Treatment with 6 microM API-59CJ-OME resulted in preferential cell death in Ishikawa and RL95 cells compared to another endometrial cancer cell line, ECC1 after 48 h of treatment. API-59CJ-OME treatment of Ishikawa cells resulted in cell cycle arrest in the G2/M phase. The addition of API-59CJ-OME to carboplatin resulted in a synergistic increase in cell death by apoptosis compared to the responses to each agent separately. Treatment with API-59CJ-OME, carboplatin, paclitaxel or the combinations for 24 h increased nuclear expression of FOXO1 in Ishikawa cells. Overexpression of FOXO1 caused 37% of the cells to die within 24 h. Addition of carboplatin to the AD-FOXO1 expressing cells further increased cell death to 71%. CONCLUSIONS: Inhibition of AKT signaling potentiates cell death in Ishikawa and RL95 cells when combined with carboplatin through mechanisms involving FOXO1 activation.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Elipticinas/farmacología , Neoplasias Endometriales/tratamiento farmacológico , Factores de Transcripción Forkhead/metabolismo , Proteínas Proto-Oncogénicas c-akt , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Carboplatino/administración & dosificación , Carboplatino/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Elipticinas/administración & dosificación , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Citometría de Flujo , Proteína Forkhead Box O1 , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Transducción de Señal/efectos de los fármacos

RESUMEN

Differentiation of human endometrial stromal cells (HESCs) into decidual cells is associated with induction of the forkhead transcription factor forkhead box O1A (FOXO1). We performed a genomic screen to identify decidua-specific genes under FOXO1 control. Primary HESCs were transfected with small interfering RNA targeting FOXO1 or with nontargeting control small interfering RNA before treatment with a cAMP analogue and the progestin, medroxyprogesterone acetate for 72 h. Total RNA was processed for whole genome analysis using high-density oligonucleotide arrays. We identified 3405 significantly regulated genes upon decidualization of HESCs, 507 (15.3%) of which were aberrantly expressed upon FOXO1 knockdown. Among the most up-regulated FOXO1-dependent transcriptional targets were WNT signaling-related genes (WNT4, WNT16 ), the insulin receptor (INSR), differentiation markers (PRL, IGFBP1, and LEFTY2), and the cyclin-dependent kinase inhibitor p57(Kip2) (CDKN1C). Analysis of FOXO1-dependent down-regulated genes uncovered several factors involved in cell cycle regulation, including CCNB1, CCNB2, MCM5, CDC2 and NEK2. Cell viability assay and cell cycle analysis demonstrated that FOXO1 silencing promotes proliferation of differentiating HESCs. Using a glutathione-S-transferase pull-down assay, we confirmed that FOXO1 interacts with progesterone receptor, irrespectively of the presence of ligand. In agreement, knockdown of PR disrupted the regulation of FOXO1 target genes involved in differentiation (IGFBP1, PRL, and WNT4) and cell cycle regulation (CDKN1, CCNB2 and CDC2) in HESCs treated with either cAMP plus medroxyprogesterone acetate or with cAMP alone. Together, the data demonstrate that FOXO1 engages in transcriptional cross talk with progesterone receptor to coordinate cell cycle regulation and differentiation of HESCs.

Asunto(s)

Diferenciación Celular/genética , Endometrio/metabolismo , Factores de Transcripción Forkhead/metabolismo , Regulación del Desarrollo de la Expresión Génica , Receptores de Progesterona/metabolismo , Ciclo Celular/genética , Células Cultivadas , Endometrio/citología , Femenino , Proteína Forkhead Box O1 , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Células del Estroma/metabolismo , Transcripción Genética