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A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.
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INTRODUCTION: The SUDEP and Seizure Safety Checklist ("Checklist") is a risk factors Checklist based around a person with epilepsy (PWE) demographics, seizure, physical, psychological, and lifestyle issues. The Checklist provides a cumulative picture of current risk when applied to a PWE. This study compares and contrasts risk factors of PWE in primary versus secondary care. METHODS: The Checklist was applied to all PWE registered in four primary care practices in central Cornwall UK (pop: 120,000). Individual, modifiable, non-modifiable, and total risk factors and scores were compared between PWE open to secondary care and those not. Statistical tests were used to calculate significance of individual risk factors in primary or secondary care, to compare the total risk scores between care settings and to find the frequency differences of each risk factor between primary practices. RESULTS: People with total and non-modifiable risk scores were higher in secondary care (both pâ¯<â¯0.001). However, modifiable risk scores were higher in primary care (pâ¯<â¯0.001). Psychiatric concerns were the most prevalent modifiable risk factor in primary care. There were significant differences in the risk profiles between all four primary care practices. CONCLUSION: This study highlights that there is a lack of clarity on who is referred to secondary care and when. There needs to be an evidence-based system to allow for a bidirectional flow of PWE considering their fluctuating risk. The Checklist can be a decision support tool to enable this.
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Muerte Súbita e Inesperada en la Epilepsia , Muerte Súbita/epidemiología , Muerte Súbita/etiología , Humanos , Factores de Riesgo , Atención Secundaria de Salud , Convulsiones/epidemiologíaRESUMEN
In our hands, efficient access to the 4-amino-3-carboxamide disubstituted pyridine-2(1H)-one kinase hinge-binder motif proved to be more challenging than anticipated requiring a significant investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library.
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We demonstrate here, for the first time, formation of injectable dynamic covalent hydrogels at physiological pH using benzoxaborin-saccharide complexation as a reversible cross-linking method. The gels were prepared by simply mixing hyaluronic acid modified with an original boronic acid derivative, 3,4-dihydro-2H-benzo[e][1,2]oxaborinin-2-ol (1,2-ABORIN), and HA functionalized with 1-amino-1-deoxy-d-fructose. Dynamic rheological experiments confirmed the gel-like behavior (storage modulus (G') > loss modulus (Gâ³) in the frequency window explored) for the designed HA-1,2-ABORIN/HA-fructose network. Furthermore, this hydrogel exhibited excellent self-healing and injectability behaviors in aqueous conditions and was found to be responsive to pH. Additionally, fibroblast cells encapsulated in the HA network showed high viability (>80% after 7 days of cell culture), as monitored by Live/Dead staining. Taken together, this new class of boronate ester cross-linked hydrogel provides promising future for diverse biomedical applications.
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Técnicas de Cultivo de Célula/métodos , Ácido Hialurónico/química , Hidrogeles/química , Animales , Ácidos Borínicos/química , Ácidos Borónicos/química , Técnicas de Cultivo de Célula/instrumentación , Supervivencia Celular , Fibroblastos/citología , Fructosa/química , Concentración de Iones de Hidrógeno , Inyecciones , Espectroscopía de Resonancia Magnética , Ratones , ReologíaRESUMEN
Dynamic covalent hydrogels crosslinked by boronate ester bonds are promising materials for biomedical applications. However, little is known about the impact of the crosslink structure on the mechanical behaviour of the resulting network. Herein, we provide a mechanistic study on boronate ester crosslinking upon mixing hyaluronic acid (HA) backbones modified, on the one hand, with two different arylboronic acids, and on the other hand, with three different saccharide units. Combining rheology, NMR and computational analysis, we demonstrate that carefully selecting the arylboronic-polyol couple allows for tuning the thermodynamics and molecular exchange kinetics of the boronate ester bond, thereby controlling the rheological properties of the gel. In particular, we report the formation of "strong" gels (i.e. featuring slow relaxation dynamics) through the formation of original complex structures (tridentate or bidentate complexes). These findings offer new prospects for the rational design of hydrogel scaffolds with tailored mechanical response.
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Ácidos Borónicos/química , Ácido Hialurónico/química , Hidrogeles/química , Concentración de Iones de Hidrógeno , Resonancia Magnética Nuclear Biomolecular , ReologíaRESUMEN
A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
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Antineoplásicos/farmacología , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Quinina/análogos & derivados , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Modelos Moleculares , Estructura Molecular , Quinina/síntesis química , Quinina/química , Quinina/farmacología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Solubilidad , Relación Estructura-ActividadRESUMEN
Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model.
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Iminas/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Sulfonamidas/farmacología , Sulfóxidos/farmacología , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Iminas/síntesis química , Iminas/química , Ligandos , Ratones Endogámicos BALB C , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfóxidos/síntesis química , Sulfóxidos/químicaRESUMEN
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield.
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Proteína ADAM17/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Proteína ADAM17/metabolismo , Administración Tópica , Animales , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Ácidos Hidroxámicos/química , Ratones , Ratones Pelados , Microsomas Hepáticos/metabolismo , Oxazolona/toxicidad , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/prevención & control , Enfermedades de la Piel/veterinaria , Solubilidad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Anastomotic leak after colorectal surgery increases postoperative mortality, cancer recurrence, permanent stoma formation, and poor bowel function. Anastomosis between the colon and rectum is a particularly high risk. Traditional management mandates laparotomy, disassembly of the anastomosis, and formation of an often-permanent stoma. After laparoscopic colorectal surgery it may be possible to manage anastomotic failure with laparoscopy, thus avoiding laparotomy. OBJECTIVE: The purpose of this study was to determine the feasibility of the laparoscopic management of failed low colorectal anastomoses. SETTING: This was a single-institute case series. PATIENTS: A total of 555 laparoscopic patients undergoing anterior resection with primary anastomosis within 10 cm of the anus in the period 2000-2012 were included. MAIN OUTCOME MEASURES: Anastomotic failure, defined as any clinical or radiological demonstrable defect in the anastomosis; complications using the Clavien-Dindo system; mortality within 30 days; and patient demographics and risk factors, as defined by the Charlson index, were measured. RESULTS: Leakage occurred in 44 (7.9%) of 555 patients, 16 patients with a diverting ileostomy and 28 with no diverting ileostomy. Leakage was more common in those with anastomoses <5 cm form the anus, male patients, and those with a colonic J-pouch and rectal cancer. Diverting ileostomy was not protective of anastomotic leakage. In those patients with anastomotic leakage and a primary diverting ileostomy, recourse to the peritoneal cavity was required in 4 of 16 patients versus 24 of 28 without a diverting ileostomy (p = 0.0002). In 74% of those cases, access to the peritoneal cavity was achieved through laparoscopy. Permanent stoma rates were very low, including 14 (2.5%) of 555 total patients or 8 (18.0%) of 44 patients with anastomotic leakage. Thirty-day mortality was rare (0.6%). LIMITATIONS: This study was limited by the lack of a cohort of open cases for comparison. CONCLUSIONS: Laparoscopic anterior resection is associated with low levels of complications, including anastomotic leak, postoperative mortality, and permanent stoma formation. Anastomotic leakage can be managed with laparoscopy in the majority of cases. See Video Abstract at http://links.lww.com/DCR/A353.
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Fuga Anastomótica/cirugía , Enfermedades del Colon/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo , Diverticulitis/cirugía , Endometriosis/cirugía , Laparoscopía , Enfermedades del Recto/cirugía , Neoplasias del Recto/cirugía , Anastomosis Quirúrgica , Reservorios Cólicos , Bases de Datos Factuales , Estudios de Factibilidad , Femenino , Humanos , Ileostomía , Masculino , Persona de Mediana Edad , Reoperación , Factores SexualesRESUMEN
Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50â¯=â¯17â¯nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.
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4-Butirolactona/análogos & derivados , Caspasa 1/química , Inhibidores de Caspasas/química , Dipéptidos/química , 4-Butirolactona/síntesis química , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/metabolismo , Sitios de Unión , Productos Biológicos/química , Productos Biológicos/metabolismo , Caspasa 1/metabolismo , Inhibidores de Caspasas/metabolismo , Cristalografía por Rayos X , Dipéptidos/síntesis química , Dipéptidos/metabolismo , Enlace de Hidrógeno , Concentración 50 Inhibidora , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Terciaria de ProteínaRESUMEN
We report the discovery of a novel aminopyrazine series of PI3Kα inhibitors, designed by hybridizing two known scaffolds of PI3K inhibitors. We describe the progress achieved from the first compounds plagued with poor general kinase selectivity to compounds showing high selectivity for PI3Kα over PI3Kß and excellent general kinase selectivity. This effort culminated with the identification of compound 5 displaying high potency and selectivity, and suitable physiochemical and pharmacokinetic properties for oral administration. In vivo, compound 5 showed good inhibition of tumour growth (86% tumour growth inhibition at 50mg/kg twice daily orally) in the MCF7 xenograft model in mice.
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Descubrimiento de Drogas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Fosfatidilinositol 3-Quinasa Clase I , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
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Proteína ADAM17/antagonistas & inhibidores , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/química , Proteína ADAM17/metabolismo , Administración Tópica , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/enzimologíaRESUMEN
BACKGROUND: Glutathione (GSH) is a ubiquitous, non-protein biothiol in cells. It plays a variety of roles in detoxification, redox regulation and cellular signaling. Many processes that can be regulated through GSH are critical to developing systems and include cellular proliferation, differentiation and apoptosis. Understanding how GSH functions in these aspects can provide insight into how GSH regulates development and how during periods of GSH imbalance how these processes are perturbed to cause malformation, behavioral deficits or embryonic death. SCOPE OF REVIEW: Here, we review the GSH system as it relates to events critical for normal embryonic development and differentiation. MAJOR CONCLUSIONS: This review demonstrates the roles of GSH extend beyond its role as an antioxidant but rather GSH acts as a mediator of numerous processes through its ability to undergo reversible oxidation with cysteine residues in various protein targets. Shifts in GSH redox potential cause an increase in S-glutathionylation of proteins to change their activity. As such, redox potential shifts can act to modify protein function on a possible longer term basis. A broad group of targets such as kinases, phosphatases and transcription factors, all critical to developmental signaling, is discussed. GENERAL SIGNIFICANCE: Glutathione regulation of redox-sensitive events is an overlying theme during embryonic development and cellular differentiation. Various stresses can change GSH redox states, we strive to determine developmental stages of redox sensitivity where insults may have the most impactful damaging effect. In turn, this will allow for better therapeutic interventions and preservation of normal developmental signaling. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.
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Apoptosis/fisiología , Diferenciación Celular/fisiología , Proliferación Celular , Desarrollo Embrionario/fisiología , Glutatión/metabolismo , Animales , Humanos , Modelos Biológicos , Oxidación-Reducción , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: To assess the outcomes and patterns of treatment failure of patients who underwent pelvic exenteration surgery for recurrent rectal cancer. BACKGROUND: Despite advances in the management of rectal cancer, local recurrence still occurs. For appropriately selected patients, pelvic exenteration surgery can achieve long-term disease control. METHODS: Prospectively maintained databases of 5 high volume institutions for pelvic exenteration surgery were reviewed and data combined. We assessed the combined endpoints of overall 5-year survival, cancer-specific 5-year mortality, local recurrence, and the development of metastatic disease. RESULTS: Five hundred thirty-three patients who had undergone surgery for locally recurrent rectal cancer were identified. Five-year cancer-specific survival for patients with a complete (R0) resection is 44%, which was achieved in 59% of patients. For those with R1 and R2 resections, the 5-year survival was 26% and 10%, respectively. Radical resection required sacrectomy in 170 patients (32%), and total cystectomy in 105 patients (20%). Treatment failure included local recurrence alone in 75 patients (14%) and systemic metastases with or without local recurrence in 226 patients (42%). Chemoradiotherapy before exenteration was associated with a significant (P < 0.05) improvement in overall 5-year cancer-specific survival for those patients with an R0 resection. Postoperative chemotherapy did not alter outcomes. CONCLUSIONS: R0 resection of the pelvic recurrence is the most significant factor affecting overall and disease-free survival. The surgery is complex and often highly morbid, and where possible patients should be given perioperative chemoradiotherapy. Further investigations are required to determine the role of adjuvant chemotherapy.
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Recurrencia Local de Neoplasia/cirugía , Exenteración Pélvica , Neoplasias del Recto/cirugía , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Estudios Retrospectivos , Tasa de Supervivencia , Insuficiencia del TratamientoRESUMEN
Targeting the IL17 pathway and more specifically the nuclear receptor RORγ is thought to be beneficial in multiple skin disorders. The Letter describes the discovery of phenoxyindazoles and thiophenoxy indazoles as potent RORγ inverse agonists. Optimization of the potency and efforts to mitigate the phototoxic liability of the series are presented. Finally, crystallization of the lead compound revealed that the series bound to an allosteric site of the nuclear receptor. Such compounds could be useful as tool compounds for understanding the impact of topical treatment on skin disease models.
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Indazoles/química , Indazoles/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Agonismo Inverso de Drogas , Humanos , Simulación del Acoplamiento Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Secuencia de Aminoácidos , Sitios de Unión , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/química , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Modelos Moleculares , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/química , Proteínas Mutantes/genética , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/genética , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacologíaRESUMEN
Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kß and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.
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Antineoplásicos/farmacología , Oxadiazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Simulación del Acoplamiento Molecular , Oxadiazoles/síntesis química , Piperidinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND & AIMS: Pelvic exenteration (PE) surgery is now a widely accepted procedure that is increasingly being performed worldwide but has significant morbidity. Although nutrition status, body mass index (BMI) and postoperative nutrition support practices are modifiable risk factors, few studies have examined the relationship of these with clinical outcomes following PE. The aim of this study was therefore to investigate the impact of these factors on postoperative complications and length of hospital stay (LOHS) following PE. METHODS: This was a retrospective cohort study of all patients having total PE surgery at a tertiary teaching hospital from 2012 to 2021 (n = 69). Multivariable analyses were undertaken to confirm univariate associations and adjust for confounding variables. Binary logistic regression was undertaken to explore predictors of infectious and Grade III or above Clavien-Dindo complications, and negative binomial regression to identify predictors of LOHS. RESULTS: Patients who were malnourished according to the Subjective Global Assessment were 5.66 (OR 5.66, 95% CI 1.07-29.74, p = 0.041) times more likely to develop an infectious complication. Increasing BMI was independently associated with development of Grade III or above Clavien-Dindo complications (p = 0.040). For each additional day until full diet commencement, there was a 19% (OR: 1.19, 95% CI 1.05-1.34, p = 0.005) increased incidence of significant complications and a 5.6% (IRR: 1.056, 95% CI: 1.02-1.09, p = 0.002) longer LOHS on multivariable analysis. There was a high rate of prolonged postoperative ileus (78%). The implementation of a nutrition support pathway with routine postoperative parenteral nutrition (PN) resulted in patients achieving adequate nutrition 7 days faster (p < 0.001) with minimal line-related complications (1.4% line-related thrombus). Routine PN did not impact ileus rates (p = 0.33) or time to diet commencement (p = 0.6). CONCLUSIONS: Preoperative malnutrition and higher BMI were associated with complications following PE. Delay to full diet commencement was associated with increased complications and longer LOHS. Routine postoperative PN appears safe and resulted in patients achieving adequate nutrition faster.
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Índice de Masa Corporal , Tiempo de Internación , Estado Nutricional , Exenteración Pélvica , Complicaciones Posoperatorias , Humanos , Femenino , Estudios Retrospectivos , Masculino , Complicaciones Posoperatorias/epidemiología , Persona de Mediana Edad , Anciano , Factores de Riesgo , Desnutrición , Adulto , Apoyo NutricionalRESUMEN
Di-2-ethylhexyl phthalate (DEHP) is an environmental contaminant commonly used as a plasticizer in polyvinyl chloride products. Exposure to DEHP has been linked to adverse pregnancy outcomes in humans including preterm birth, low birth-weight, and pregnancy loss. Although oxidative stress is linked to the pathology of adverse pregnancy outcomes, effects of DEHP metabolites, including the active metabolite, mono-2-ethylhexyl phthalate (MEHP), on oxidative stress responses in placental cells have not been previously evaluated. The objective of the current study is to identify MEHP-stimulated oxidative stress responses in human placental cells. We treated a human placental cell line, HTR-8/SVneo, with MEHP and then measured reactive oxygen species (ROS) generation using the dichlorofluorescein assay, oxidized thymine with mass-spectrometry, redox-sensitive gene expression with qRT-PCR, and apoptosis using a luminescence assay for caspase 3/7 activity. Treatment of HTR-8 cells with 180µM MEHP increased ROS generation, oxidative DNA damage, and caspase 3/7 activity, and resulted in differential expression of redox-sensitive genes. Notably, 90 and 180µM MEHP significantly induced mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2), an enzyme important for synthesis of prostaglandins implicated in initiation of labor. The results from the present study are the first to demonstrate that MEHP stimulates oxidative stress responses in placental cells. Furthermore, the MEHP concentrations used were within an order of magnitude of the highest concentrations measured previously in human umbilical cord or maternal serum. The findings from the current study warrant future mechanistic studies of oxidative stress, apoptosis, and prostaglandins as molecular mediators of DEHP/MEHP-associated adverse pregnancy outcomes.
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Dietilhexil Ftalato/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Placenta/efectos de los fármacos , Plastificantes/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/fisiología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Daño del ADN , Dietilhexil Ftalato/toxicidad , Femenino , Humanos , Estrés Oxidativo/fisiología , Placenta/metabolismo , Embarazo , ARN Mensajero/química , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Timina/metabolismoRESUMEN
Schwannoma (neurilemmoma) originating from the pulmonary artery has not before been described. A 65 year-old male presented with dyspnoea on exertion. CT scan was negative for pulmonary thromboembolism, but showed a well circumscribed, heterogeneous mass, 52 mm × 45 mm × 41 mm, straddling the left pulmonary artery and compressing the left atrium. The mass was found at surgery to be originating from the lateral wall of the left pulmonary artery. The tumour was completely resected, and the pulmonary artery reconstructed. The mass was found to be a benign schwannoma on histopathology.