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2.
Ann Surg Oncol ; 31(10): 7133-7141, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39012464

RESUMO

BACKGROUND: Patients with peritoneal carcinomatosis often suffer from loss of skeletal muscle mass and require extensive surgery. Multimodal prehabilitation may improve physical status but its benefits for these specific patients remain unknown. This study aimed to evaluate the effect of prehabilitation on functional walking capacity and skeletal muscle mass, as well as its association with postoperative complications. PATIENTS AND METHODS: A prospective study of patients with peritoneal carcinomatosis following a home-based trimodal prehabilitation program was carried out. Functional walking capacity was assessed with the 6-min walk test (T6MWT), and by the appendicular skeletal muscle index (ASMI) estimated by bioelectrical impedance analysis. Data were collected at the first medical appointment and on the day before surgery. A 90-day postoperative morbidity was registered according to the Clavien-Dindo classification. RESULTS: A total of 62 patients were included in the analysis. Women were more prevalent (77.4%) and peritoneal metastasis from ovarian origin accounted for 48.4%. Clavien II-V grades occurred in 30 (57.7%) patients. After prehabilitation, functional walking capacity improved by 42.2 m (39.62-44.72 m) compared with baseline data (p < 0.001), but no improvement was observed in the ASMI (p = 0.301). Patients able to walk at least 360 m after prehabilitation suffered fewer Clavien-Dindo II-V postoperative complications (p = 0.016). A T6MWT of less than 360 m was identified as an independent risk factor in the multivariable analysis (OR 3.99; 1.01-15.79 p = 0.048). CONCLUSIONS: This home-based trimodal prehabilitation program improved functional walking capacity but not ASMI scores in patients with peritoneal metastasis before surgery. A T6MWT of less than 360 m was found to be a risk factor for postoperative complications.


Assuntos
Procedimentos Cirúrgicos de Citorredução , Músculo Esquelético , Neoplasias Peritoneais , Exercício Pré-Operatório , Caminhada , Humanos , Feminino , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/cirurgia , Masculino , Estudos Prospectivos , Pessoa de Meia-Idade , Caminhada/fisiologia , Seguimentos , Prognóstico , Complicações Pós-Operatórias/prevenção & controle , Idoso , Adulto
3.
Br J Surg ; 108(10): 1149-1153, 2021 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33864061

RESUMO

Clinical decision-making in the treatment of patients with obstructed defaecation remains controversial and no international guidelines have been provided so far. This study reports a consensus among European opinion leaders on the management of obstructed defaecation in different possible clinical scenarios.


Assuntos
Tomada de Decisão Clínica , Constipação Intestinal/diagnóstico , Constipação Intestinal/cirurgia , Defecação , Obstrução Intestinal/diagnóstico , Obstrução Intestinal/cirurgia , Algoritmos , Constipação Intestinal/fisiopatologia , Humanos , Obstrução Intestinal/fisiopatologia , Síndrome
4.
Proc Natl Acad Sci U S A ; 117(42): 26366-26373, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33024016

RESUMO

Agrobacterium tumefaciens C58 contains four replicons, circular chromosome (CC), linear chromosome (LC), cryptic plasmid (pAt), and tumor-inducing plasmid (pTi), and grows by polar growth from a single growth pole (GP), while the old cell compartment and its old pole (OP) do not elongate. We monitored the replication and segregation of these four genetic elements during polar growth. The three largest replicons (CC, LC, pAt) reside in the OP compartment prior to replication; post replication one copy migrates to the GP prior to division. CC resides at a fixed location at the OP and replicates first. LC does not stay fixed at the OP once the cell cycle begins and replicates from varied locations 20 min later than CC. pAt localizes similarly to LC prior to replication, but replicates before the LC and after the CC. pTi does not have a fixed location, and post replication it segregates randomly throughout old and new cell compartments, while undergoing one to three rounds of replication during a single cell cycle. Segregation of the CC and LC is dependent on the GP and OP identity factors PopZ and PodJ, respectively. Without PopZ, replicated CC and LC do not efficiently partition, resulting in sibling cells without CC or LC. Without PodJ, the CC and LC exhibit abnormal localization to the GP at the beginning of the cell cycle and replicate from this position. These data reveal PodJ plays an essential role in CC and LC tethering to the OP during early stages of polar growth.


Assuntos
Agrobacterium tumefaciens/genética , Segregação de Cromossomos/genética , Replicon/genética , Agrobacterium tumefaciens/crescimento & desenvolvimento , Proteínas de Bactérias/metabolismo , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/genética , Cromossomos Bacterianos/metabolismo
5.
Sci Rep ; 10(1): 11519, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32636438

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

7.
Sci Rep ; 10(1): 7346, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355193

RESUMO

The impact of an enhanced recovery after surgery (ERAS) programme in emergency colorectal surgery has not yet been reported. The objective of this study was to evaluate the feasibility and the results of patients included in an ERAS protocol following emergency colon surgery for left colon perforation. For this purpose, patients with a low to moderate risk of mortality, according to a Peritonitis Severity Score (PSS), and treated with an ERAS protocol (ERAS group) after emergency surgery for left colon perforation were compared for a period of 40 months (March 2014-June 2017) with a control group of patients treated with conventional care (CC group) during the 38 months prior to implementation of the new ERAS protocol (January 2011-February 2014). The main endpoint was 90-day postoperative morbidity according to the Clavien-Dindo classification. Secondary endpoints included length of postoperative hospital stay, 90-day readmission rate, protocol compliance and mortality. Fifty patients were included in the study, 29 in the ERAS group and 21 in the CC group. There were no significant differences between the groups in the demographic data or in the operative characteristics. A reduction in the incidence of postoperative complications (20.7% vs. 38%; p > 0.05) and in the postoperative hospital stay (7.7 + /- 3.85 vs. 10.9 + /- 5.6 days; p = 0.009) were observed in the ERAS group. The 90-day readmission rate did not differ significantly between the two groups (2 vs. 1). No 90-day mortality was observed in either group. The ERAS group showed better results than the CC group in protocol compliance. We conclude that ERAS protocols are feasible and help to reduce morbidity and length of hospital stay without adversely affecting the rate of readmission or mortality.


Assuntos
Colo/cirurgia , Doenças do Colo/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Complicações Pós-Operatórias , Estudos Prospectivos , Estudos Retrospectivos
8.
Leukemia ; 34(10): 2648-2659, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32107471

RESUMO

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.


Assuntos
MicroRNAs/genética , Transtornos Mieloproliferativos/genética , Mielofibrose Primária/genética , Idoso , Alelos , Animais , Citocinas/genética , Progressão da Doença , Feminino , Genótipo , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Transtornos Mieloproliferativos/patologia , NF-kappa B/genética , Policitemia Vera/genética , Policitemia Vera/patologia , Transdução de Sinais/genética , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia
12.
Br J Anaesth ; 122(2): 180-187, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30686303

RESUMO

BACKGROUND: Systemic inflammation is pivotal in the pathogenesis of cardiovascular disease. As inflammation can directly cause cardiomyocyte injury, we hypothesised that established systemic inflammation, as reflected by elevated preoperative neutrophil-lymphocyte ratio (NLR) >4, predisposes patients to perioperative myocardial injury. METHODS: We prospectively recruited 1652 patients aged ≥45 yr who underwent non-cardiac surgery in two UK centres. Serum high sensitivity troponin T (hsTnT) concentrations were measured on the first three postoperative days. Clinicians and investigators were blinded to the troponin results. The primary outcome was perioperative myocardial injury, defined as hsTnT≥14 ng L-1 within 3 days after surgery. We assessed whether myocardial injury was associated with preoperative NLR>4, activated reactive oxygen species (ROS) generation in circulating monocytes, or both. Multivariable logistic regression analysis explored associations between age, sex, NLR, Revised Cardiac Risk Index, individual leukocyte subsets, and myocardial injury. Flow cytometric quantification of ROS was done in 21 patients. Data are presented as n (%) or odds ratio (OR) with 95% confidence intervals. RESULTS: Preoperative NLR>4 was present in 239/1652 (14.5%) patients. Myocardial injury occurred in 405/1652 (24.5%) patients and was more common in patients with preoperative NLR>4 [OR: 2.56 (1.92-3.41); P<0.0001]. Myocardial injury was independently associated with lower absolute preoperative lymphocyte count [OR 1.80 (1.50-2.17); P<0.0001] and higher absolute preoperative monocyte count [OR 1.93 (1.12-3.30); P=0.017]. Monocyte ROS generation correlated with NLR (r=0.47; P=0.03). CONCLUSIONS: Preoperative NLR>4 is associated with perioperative myocardial injury, independent of conventional risk factors. Systemic inflammation may contribute to the development of perioperative myocardial injury. CLINICAL TRIAL REGISTRATION: NCT01842568.


Assuntos
Traumatismos Cardíacos/etiologia , Procedimentos Cirúrgicos Operatórios/métodos , Síndrome de Resposta Inflamatória Sistêmica/complicações , Idoso , Estudos de Coortes , Feminino , Humanos , Complicações Intraoperatórias/etiologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Resultado do Tratamento , Troponina T/sangue
13.
Eur J Pharm Sci ; 119: 22-30, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29626594

RESUMO

BACKGROUND: The evaluation of the efficacy and toxicity of hyperthermic intraoperative peritoneal chemotherapy presents some difficulties, due in part to the lack of information about the pharmacokinetic behavior of the drugs administered in this procedure. The aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters. METHODS: Oxaliplatin peritoneal and plasma concentrations from 37 rats treated by either intravenous or intraperitoneal oxaliplatin administrations under different instillation times, temperatures and doses were analyzed according to a population pharmacokinetic approach using the software NONMEM V7.3®. RESULTS: Intraperitoneal (n = 115) and plasma (n = 263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distribution were 3.25 mL/min (39.1%), 53.6 mL (37.8%) and 54.1 mL (77.3%), respectively. Clearance decreased to 0.151 mL/min (39.1%) when the instillation was still ongoing, at 31.4 min. One of the possible reasons behind the clearance decrease would be an alteration of renal function due to surgery and/or hyperthermia. CONCLUSIONS: This study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters.


Assuntos
Antineoplásicos/farmacocinética , Hipertermia Induzida , Modelos Biológicos , Compostos Organoplatínicos/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Terapia Combinada , Injeções Intraperitoneais , Masculino , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/sangue , Oxaliplatina , Peritônio/metabolismo , Ratos Wistar
14.
Semergen ; 44(2): 90-99, 2018 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-28190672

RESUMO

OBJECTIVES: The aim of this study was to perform a bibliometric analysis of EPI-SCAN and IBERPOC studies using the Science Citation Index and Scopus databases, and to determine the overall impact with the impact of smoking on IBERPOC as a secondary objective. METHOD: A general searching was conducted in Science Citation Index-Expanded through the Web of Science (WoS) (Thomson Reuters) platform and Scopus on 23 March 2015. The search strategy included the terms "iberpoc" OR "episcan" was performed on 15 October 2015. RESULTS: A total of 24 publications were obtained; 13 from IBERPOC study (9 on "COPD" and 4 for "tobacco"), with 11 from the EPI-SCAN (All COPD) study. A total of 841 WoS citations were obtained (445 IBERPOC [99 of tobacco]), and 1,442 from Scopus (963 IBERPOC [144 tobacco]). The theme "tobacco" contributed with 22.24% and 14.95% of total citations in WoS and Scopus, respectively to the IBERPOC study. It was found that Scopus citations were newer, and a similar impact from both WoS studies was detected, although the IBERPOC impact was greater in Scopus. Collaborative networks of institutions and authors of both studies were identified. CONCLUSIONS: There is an important productivity and impact of both studies. Scopus citations are newer than those in WoS. The "tobacco" variable added IBERPOC impact and visibility. There was high density, accessibility, and cohesion in collaborative networks of both studies.


Assuntos
Publicações Periódicas como Assunto/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologia , Bibliometria , Comportamento Cooperativo , Humanos , Editoração/estatística & dados numéricos , Projetos de Pesquisa , Fumar/efeitos adversos
15.
Rev. peru. med. exp. salud publica ; 3(2): 78-84, 2018. tab, graf, ilus
Artigo em Espanhol | MOSAICO - Saúde integrativa, LILACS | ID: biblio-1145637

RESUMO

Objetivo. Determinar la toxicidad a dosis repetidas durante 28 días, de la ingestión por vía oral del agua termal de San Antonio de Putina-SAP-(Puno), en un modelo murino. Materiales y métodos. Diseño experimental, se utilizaron diez ratas de experimentación de cepa Holtzman, los que fueron divididos en dos grupos de cinco cada uno: un grupo de estudio, al que se le administró en forma repetida, agua termal traída de SAP, en una dosis de 1000 mg/kg en un volumen de 2 mL/100g, y un grupo control con agua potable esterilizada en el mismo volumen. Se realizaron observaciones clínicas diarias, determinación semanal del peso corporal, y después de 28 días se procedió con el estudio histopatológico de órganos (corazón, riñón, hígado y pulmón) y la determinación de parámetros hematológicos y bioquímicos; previo sacrificio de los animales de experimentación. Resultados. No se produjeron muertes (DL50> 1000 mg/kg) ni alteraciones permanentes de signos clínicos. Se observó aumento de peso, sin diferencias estadísticas entre los grupos. Los resultados hematológicos y bioquímicos reflejaron ligeras variaciones no significativas entre grupos, pero dentro del rango de la normalidad. No se observaron alteraciones histopatológicas. Conclusiones. No se encontraron signos de toxicidad aguda ante la administración de agua termomineral de San Antonio de Putina (Puno) en dosis repetidas por un periodo de 28 días.


Objective. To determine 28-day oral acute toxicity at repeated doses of hot springs water from San Antonio de Putina ­SAP- (Puno) in rats. Materials and methods. Experimental design, ten Holtzman rats were used, which were divided into two groups of five each: a study group that was exposed to repeated administration of SAP hot spring water in a dose of 1000 mg / kg in a volume of 2 mL/100g; and a control group, which sterilized water was given in the same volume. Daily clinical observations were made, weekly determination of body weight; and after 28 days; previous sacrifice of animals, the histopathological study of organs (heart, kidney, liver and lung) and determination of hematological and biochemical parameters were made. Results. No deaths (LD50> 1000 mg/kg) or permanent alterations of clinical signs were observed. Weight gain without statistical differences between the groups was observed. The hematological and biochemical results showed slight nonsignificant variations between groups, but in normality levels. No histopathological alterations were observed. Conclusions. No signs of acute toxicity were found after 28-days repeated administration of hot spring water from San Antonio de Putina (Puno).


Assuntos
Animais , Ratos , Balneologia , Testes de Toxicidade Aguda , Fontes Termais , Peru , Terapias Complementares , Medicina Tradicional
16.
Med. interna Méx ; 33(5): 563-571, sep.-oct. 2017. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-894299

RESUMO

Resumen ANTECEDENTES: la pandemia de influenza en 2009 renovó el interés por identificar oportunamente casos sospechosos de influenza mediante estudios de laboratorio rutinarios, uno de los más estudiados es la deshidrogenasa láctica (DHL). OBJETIVO: determinar si los pacientes con neumonía por influenza A (H1N1) tienen alteraciones particulares en estudios rutinarios de laboratorio, particularmente en concentraciones de DHL y analizar la implicación pronóstica. MATERIAL Y MÉTODO: estudio de casos y controles de pacientes con diagnóstico confirmado de neumonía por influenza A (H1N1) [caso], y pacientes con neumonía bacteriana (control) atendidos de diciembre de 2013 a julio de 2014. RESULTADOS: se analizaron 31 casos, 45% (n = 14) tenían diagnóstico de neumonía por el virus de la influenza A (H1N1), el 55% restante (n = 17) se consideró de causa bacteriana. La media de edad fue de 38 años (límites: 16-62). Las concentraciones de DHL al momento del diagnóstico fueron, en promedio, de 578.77 UI/L (límites: 191-1096), fue mayor en el grupo con neumonía por influenza A (H1N1) [573 vs 624.7 UI/L, p = 0.366]. En el análisis global las concentraciones de DHL > 350 UI/L al diagnóstico y fin del tratamiento repercutieron fuertemente de manera negativa en la mortalidad (OR: 84.0, IC95%: 4.4754-1576.6044 y OR: 154.0, 8.6261-2749.3255). La supervivencia general fue de 18 días, menor en el grupo de A (H1N1) [4 vs 25 días, p = 0.016). CONCLUSIONES: las concentraciones de DHL > 350 UI/L pueden considerarse un biomarcador de gravedad y repercuten negativamente en la supervivencia de pacientes con neumonía, sin poder discriminar al posible agente etiológico.


Abstract BACKGROUND: The 2009 influenza pandemic renewed interest in timely identification of suspected influenza cases through routine laboratory studies, the most studied is lactic dehydrogenase (DHL). OBJECTIVE: To determine if patients with influenza A (H1N1) pneumonia present particular alterations inside routine laboratory studies, particularly in DHL levels and analyze the prognostic implication. MATERIAL AND METHOD: A case-control study of patients with confirmed diagnosis of influenza A (H1N1) pneumonia (case), and patients with bacterial pneumonia (control) treated from December 2013 to July 2014. RESULTS: Thirty-one cases were analyzed, 45% (n = 14) had a diagnosis of influenza A (H1N1) pneumonia, the remaining 55% (n = 17) was considered of bacterial etiology. The mean age was 38 (16-62) years old. The DHL level at diagnosis time was on average 578.77 IU/L (191-1096), higher in the group with influenza A (H1N1) pneumonia (573 IU/L vs 624.7 IU/L, p = 0.366). In the overall analysis, the levels of DHL > 350 IU/L at diagnosis time and at the end of treatment had a negative impact on mortality (OR: 84.0, 95%CI: 4.4754-1576.6044, and OR: 154.0, 8.6261-2749.3255). Overall survival was 18 days, lower in the A (H1N1) group (4 vs 25 days, p = 0.016). CONCLUSIONS: DHL > 350 IU/L can be considered a severity biomarker, also has a negative impact on the survival of patients with pneumonia without being able to discriminate the possible etiological agent.

17.
Tech Coloproctol ; 21(2): 149-153, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28108825

RESUMO

BACKGROUND: Photodynamic therapy (PDT) is a new procedure for the treatment of anal fistula. This preliminary study was designed to investigate the safety and effectiveness of this new technique in the treatment of anal fistula. METHODS: Ten patients were treated with PDT. Intralesional 5-aminolevulinic acid (ALA) 2% was directly injected into the fistula. The internal and external orifices were closed. After an incubation period of 2 h, the fistula was irradiated using an optical fibre connected to a red laser (MULTIDIODE 630 PDT, INTERmedic, Spain) operating at 1 W/cm for 3 min (180 Joules). Patient demographics, operation notes and complications were recorded. RESULTS: There were no complications. The average length of patient follow-up was 14.9 months (range 12-20 months). We could observe primary healing in eight patients (80%). Two patients (20%) showed persistence of suppuration after the operation. No patient reported incontinence postoperatively. CONCLUSIONS: PDT is a potential sphincter-saving procedure that is safe, simple and minimally invasive and has a high success rate.


Assuntos
Ácido Aminolevulínico/administração & dosagem , Terapia a Laser/métodos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fístula Retal/tratamento farmacológico , Adolescente , Adulto , Idoso , Anti-Infecciosos/administração & dosagem , Antibioticoprofilaxia/métodos , Terapia Combinada , Feminino , Seguimentos , Humanos , Injeções , Masculino , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Tobramicina/administração & dosagem , Resultado do Tratamento , Adulto Jovem
18.
PLoS One ; 11(7): e0158634, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27462980

RESUMO

BACKGROUND: A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models. METHODS: An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient-derived neurospheres (TS543) and U251 cells, with different degrees of blood-brain barrier (BBB) disruption were also used for PET imaging experiments. RESULTS: 89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models. CONCLUSION: A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In vivo validation showed high-specific-contrast imaging of MT1-MMP positive GBM tumors and provided strong evidence for utility of MT1-MMP-targeted immunoPET as an alternate to nonspecific imaging of GBM.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Metaloproteinase 14 da Matriz/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Anticorpos Monoclonais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/enzimologia , Linhagem Celular Tumoral , Glioblastoma/enzimologia , Humanos , Metaloproteinase 14 da Matriz/imunologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , Prognóstico , Microtomografia por Raio-X
19.
J Thromb Haemost ; 14(6): 1226-37, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26999003

RESUMO

UNLABELLED: Essentials Estrogens are known to influence the expression of microRNAs in breast cancer cells. We looked at microRNAs in estrogenic regulation of tissue factor pathway inhibitor α (TFPIα). Estrogen upregulated microRNA-27a/b and microRNA-494 through the estrogen receptor α. MicroRNA-27a/b and microRNA-494 are partly involved in estrogenic downregulation of TFPIα. SUMMARY: Background Tissue factor pathway inhibitor (TFPI) has been linked to breast cancer pathogenesis. We have recently reported TFPI mRNA levels to be downregulated by estrogens in a breast cancer cell line (MCF7) through the estrogen receptor α (ERα). Accumulating evidence also indicates that activation of ERα signaling by estrogens may modulate the expression of target genes indirectly through microRNAs (miRNAs). Objectives To examine if miRNAs are involved in the estrogenic downregulation of TFPIα. Methods Computational analysis of the TFPI 3'-untranslated region (UTR) identified potential binding sites for miR-19a/b, miR-27a/b, miR-494, and miR-24. Transient overexpression or inhibition of the respective miRNAs was achieved by transfection of miRNA mimics or inhibitors. Direct targeting of TFPI 3'-UTR by miR-27a/b and miR-494 was determined by luciferase reporter assay in HEK293T cells. Effects of 17α-ethinylestradiol (EE2) and fulvestrant on relative miR-27a/b, miR-494, and TFPI mRNA levels in MCF7 cells were determined by qRT-PCR and secreted TFPIα protein by ELISA. Transient knockdown of ERα was achieved by siRNA transfection. Results EE2 treatment lead to a significant increase in miR-19a, miR-27a/b, miR-494, and miR-24 mRNA levels in MCF7 cells through ERα. miR-27a/b and miR-494 mimics lead to reduced TFPI mRNA and protein levels. Luciferase assay showed direct targeting of miR-27a/b and miR-494 on TFPI mRNA. Impaired estrogen-mediated downregulation of TFPI mRNA was detected in anti-miR-27a/b and anti-miR-494 transfected cells. Conclusions Our results provide evidence that miR-27a/b and miR-494 regulate TFPIα expression and suggest a possible role of these miRNAs in the estrogen-mediated downregulation of TFPIα.


Assuntos
Regulação para Baixo , Estrogênios/química , Lipoproteínas/metabolismo , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Sítios de Ligação , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Fator Xa/química , Células HEK293 , Humanos , Células MCF-7 , Ligação Proteica , Transfecção
20.
Int J Colorectal Dis ; 31(2): 197-210, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26507962

RESUMO

PURPOSE: To obtain a prognostic index, which has been named PROCOLE (prognostic colorectal leakage), it can predict the risk that a certain individual may suffer anastomotic leakage. METHODS: The methodology consists of a systematic review to identify potential risk factors for anastomotic leakage and a meta-analysis of studies of each of these factors. In the meta-analysis, the prognostic index integrates factors that are statistically significant, which are weighted according to the estimated value of the effect size. The prognostic index was validated using retrospectively collected data from patients who underwent colorectal cancer surgery anastomosis at our institution. RESULTS: The mean and standard deviation of the PROCOLE prognostic index in patients with anastomotic leakage is 1.9 ± 6.13, whereas in controls, it is 3.63 ± 2.1. The predictive ability of the PROCOLE, assessed by calculating the area under the curve (AUC) of the receiver operating characteristic (ROC), results in an AUC of 0.82 with a 95% confidence interval (CI) (0.75, 0.89) of the AUC, and it can be considered a good prognostic indicator. CONCLUSIONS: The PROCOLE prognostic index predicts the risk of a certain individual developing anastomotic leakage after colorectal cancer surgery. Specifically, the PROCOLE prognostic index establishes a discrimination value threshold of 4.83 for recommending the implementation of a protective stoma. We have developed free software with a simple interface that only requires the selection of risk factors to obtain the PROCOLE value.


Assuntos
Fístula Anastomótica/etiologia , Colo/cirurgia , Neoplasias Colorretais/cirurgia , Reto/cirurgia , Humanos , Estudos Observacionais como Assunto , Prognóstico , Fatores de Risco
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