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RESEARCH QUESTION: To investigate whether patient factors influence the decision to freeze a blastocyst with low implantation potential. DESIGN: This experimental study assessed 170 practicing embryologists from a variety of countries who were recruited via an online survey. Participants were currently practicing embryologists, who grade blastocysts as part of this role. The survey presented decision-making 'vignettes' to participants. These included specific patient information, as well as an image of an expanded blastocyst that was of borderline quality for inner cell mass and trophectoderm, for which the embryologist selected whether or not to freeze. High/low maternal age, the presence/absence of other top quality blastocysts, and the presence/absence of previously unsuccessful IVF cycles were systematically varied within the patient information in a 2 × 2 × 2 design. Participants reported how likely they would be to freeze a particular blastocyst on a scale of 1 (Extremely Unlikely) to 7 (Extremely Likely), and whether or not they would ultimately freeze each blastocyst (Yes or No). RESULTS: Lower maternal age, no other high-quality blastocysts within the cohort, and multiple unsuccessful IVF cycles were associated with greater likelihood of recommending to freeze (P < .001). Furthermore, significant interactions among all three patient factors were noted. CONCLUSION: This study provides evidence suggesting that when faced with an uncertain blastocyst, factors pertaining to the patient (maternal age, the presence/absence of other top quality blastocysts, and the presence/absence of previously unsuccessful IVF cycles) influence the decision to freeze.
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Blastocisto/fisiología , Técnicas de Cultivo de Embriones , Implantación del Embrión/fisiología , Desarrollo Embrionario/genética , Adulto , Estudios de Cohortes , Criopreservación , Implantación del Embrión/genética , Transferencia de Embrión , Femenino , Congelación/efectos adversos , Humanos , Nacimiento Vivo , EmbarazoRESUMEN
BACKGROUND: Anti-tumour necrosis factor (TNF) and anti-interleukin (IL)-12/23 biologics revolutionized plaque psoriasis treatment by enabling ≥75% improvement in the Psoriasis Area and Severity Index (PASI 75) in clinical trials. Modern biologics are now reported to achieve PASI 100 (complete skin clearance) in clinical trials. However, real-world evidence of skin clearance rates with biologics is limited. PSO-BIO-REAL was conducted to understand the real-world burden of plaque psoriasis. OBJECTIVE: The primary objective of this observational study was to estimate the proportion of patients who achieved complete skin clearance at 6 months. Secondary objectives included maintenance of response and evaluation of complete skin clearance at 12 months. METHODS: PSO-BIO-REAL was a multinational, prospective, real-world, non-interventional study of skin clearance and patient-reported outcomes (PROs) with biologics. A total of 846 patients from the United States (32%), France (28%), Italy (22%), the United Kingdom (11%) and Germany (8%) were enrolled and followed for one year. Eligible patients were aged ≥18 years with moderate-to-severe plaque psoriasis who had initiated a biologic for plaque psoriasis. Patients could be biologic-naïve or switching biologics (biologic-experienced). Assessments were made at baseline and at months 6 and 12. RESULTS: At 6 and 12 months, 23% and 26% of patients achieved complete skin clearance, respectively. Prior to study entry, 60% were biologic-naïve. The proportion of patients achieving complete skin clearance was lower among biologic-experienced patients (20% at both months 6 and 12) compared with biologic-naïve patients (25% at month 6, 30% at month 12). The rate of complete skin clearance decreased as the number of prior biologics and baseline comorbidities increased. CONCLUSION: Only one in four patients achieved complete skin clearance after 6 months of treatment with biologics. The study indicates there still is an unmet need for more efficacious biologics for patients with psoriasis.
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Productos Biológicos , Psoriasis , Adolescente , Adulto , Productos Biológicos/uso terapéutico , Francia , Alemania , Humanos , Italia , Estudios Prospectivos , Psoriasis/tratamiento farmacológico , Reino UnidoRESUMEN
PURPOSE: Quantitative computed tomography (QCT)-derived measures of lung density are valued methods for objectively characterizing lung parenchymal and peripheral airways disease and are being used in a growing number of lung disease focused trials. Detector and reconstruction improvements in CT technology have allowed for significant radiation dose reduction in image acquisition with comparable qualitative image quality. We report the impact of detector type and reconstruction type on QCT lung density measures in relation to decreasing dose indices. METHODS: Two sets of studies were completed in an in vivo pig model with a SOMATOM Definition Flash CT system: (a) prior to system upgrade with conventional detectors (UFC) and filtered back projection (FBP), and (b) post system upgrade with integrated electronic detectors (STELLAR) and iterative reconstruction (SAFIRE). CT data were acquired across estimated CT volume dose indices (CTDIvol ) ranging from 0.75 to 15 mGy at both inspiratory and expiratory breath holds. Semiautomated lung segmentations allowed calculation of histogram median, kurtosis, and 15th percentile. Percentage of voxels below -910 HU and -950 HU (inspiratory), and -856 HU (expiratory) were also examined. The changes in these QCT metrics from dose reduction (15 mGy down to 0.75 mGy) were calculated relative to paired reference values (15 mGy). Results were compared based on detector and reconstruction type. RESULTS: In this study, STELLAR detectors improved concordance with 15 mGy values down to 3 mGy for inspiratory scans and 6 mGy for expiratory scans. The addition of SAFIRE reconstruction in all acquired measurements resulted in minimal deviation from reference values at 0.75 mGy. CONCLUSION: The use of STELLAR integrated electronic detectors and SAFIRE iterative reconstruction may allow for comparable lung density measures with CT dose indices down to 0.75 mGy.
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AIMS: To characterise and identify nationwide trends in suicide-related emergency department (ED) visits in the USA from 2006 to 2013. METHODS: We used data from the Nationwide Emergency Department Sample (NEDS) from 2006 to 2013. E-codes were used to identify ED visits related to suicide attempts and self-inflicted injury. Visits were characterised by factors such as age, sex, US census region, calendar month, as well as injury severity and mechanism. Injury severity and mechanism were compared between age groups and sex by chi-square tests and Wilcoxon rank-sum tests. Population-based rates were computed using US Census data. RESULTS: Between 2006 and 2013, a total of 3 567 084 suicide attempt-related ED visits were reported. The total number of visits was stable between 2006 and 2013, with a population-based rate ranging from 163.1 to 173.8 per 100 000 annually. The frequency of these visits peaks during ages 15-19 and plateaus during ages 35-45, with a mean age at presentation of 33.2 years. More visits were by females (57.4%) than by males (42.6%); however, the age patterns for males and females were similar. Visits peaked in late spring (8.9% of all visits occurred in May), with a smaller peak in the fall. The most common mechanism of injury was poisoning (66.5%), followed by cutting and piercing (22.1%). Males were 1.6 times more likely than females to use violent methods to attempt suicide (OR = 1.64; 95% CI = 1.60-1.68; p < 0.001). The vast majority of patients (82.7%) had a concurrent mental disorder. Mood disorders were the most common (42.1%), followed by substance-related disorders (12.1%), alcohol-related disorders (8.9%) and anxiety disorders (6.4%). CONCLUSIONS: The annual incidence of ED visits for attempted suicide and self-inflicted injury in the NEDS is comparable with figures previously reported from other national databases. We highlighted the value of the NEDS in allowing us to look in depth at age, sex, seasonal and mechanism patterns. Furthermore, using this large national database, we confirmed results from previous smaller studies, including a higher incidence of suicide attempts among women and individuals aged 15-19 years, a large seasonal peak in suicide attempts in the spring, a predominance of poisoning as the mechanism of injury for suicide attempts and a greater use of violent mechanisms in men, suggesting possible avenues for further research into strategies for prevention.
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Servicio de Urgencia en Hospital/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Automutilación/epidemiología , Conducta Autodestructiva/epidemiología , Intento de Suicidio/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Intoxicación/epidemiología , Distribución por Sexo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Regions of hypoxia occur in most solid tumors, and they are associated with a poor prognostic outcome. Despite the absence of detectable DNA damage, severe hypoxia (<0.1% O2) induces a DNA damage response, including the activation of p53 and subsequent induction of p53-dependent apoptosis. Factors affecting hypoxia-induced p53-dependent apoptosis are unclear. Here we asked whether H3K9me3, through mediating gene repression, could regulate hypoxia-induced p53-dependent apoptosis. Under hypoxic conditions, increases in H3K9me3 occur in an oxygen-dependent but HIF-1-independent manner. We demonstrate that under hypoxic conditions, which induce p53 activity, the negative regulator of p53, APAK, is repressed by increases in H3K9me3 along the APAK loci. APAK repression in hypoxia is mediated by the methyltransferase SETDB1 but not Suv39h1 or G9a. Interestingly, increasing hypoxia-induced H3K9me3 through pharmacological inhibition of JMJD2 family members leads to an increase in apoptosis and decreased clonogenic survival and again correlates with APAK expression. The relevance of understanding the mechanisms of APAK expression regulation to human disease was suggested by analysis of patients with colorectal cancer, which demonstrates that high APAK expression correlates with poor prognosis. Together, these data demonstrate the functional importance of H3K9me3 in hypoxia, and they provide a novel mechanistic link between H3K9me3, p53 and apoptosis in physiologically relevant conditions of hypoxia.
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Proteínas Reguladoras de la Apoptosis/genética , Apoptosis/genética , Proteínas de Unión al ADN/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Histonas/fisiología , Proteína p53 Supresora de Tumor/fisiología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Hipoxia de la Célula/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Oxígeno/farmacología , Células Tumorales CultivadasRESUMEN
Cancer cells gain a growth advantage through the so-called Warburg effect by shifting glucose metabolism from oxidative phosphorylation to aerobic glycolysis. Hypoxia-inducible factor 1 (HIF-1) has been suggested to function in metabolic reprogramming; however, the underlying mechanism has not been fully elucidated. We found that the aberrant expression of wild-type isocitrate dehydrogenase 3α (IDH3α), a subunit of the IDH3 heterotetramer, decreased α-ketoglutarate levels and increased the stability and transactivation activity of HIF-1α in cancer cells. The silencing of IDH3α significantly delayed tumor growth by suppressing the HIF-1-mediated Warburg effect and angiogenesis. IDH3α expression was associated with the poor postoperative overall survival of lung and breast cancer patients. These results justify the exploitation of IDH3 as a novel target for the diagnosis and treatment of cancers.
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Neoplasias de la Mama/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Isocitrato Deshidrogenasa/biosíntesis , Neoplasias Pulmonares/genética , Neovascularización Patológica/genética , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Glucólisis , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Neoplasias Pulmonares/patología , Ratones , Neovascularización Patológica/patología , Fosforilación OxidativaRESUMEN
Chromatin, the structure formed by the wrapping of approximately 146 base pairs of DNA around an octamer of histones, has a profound impact on numerous DNA-based processes. Chromatin modifications and chromatin remodellers have recently been implicated in important aspects of the DNA damage response including facilitating the initial sensing of the damage as well as subsequent recruitment of repair factors. Radiation is an effective cancer therapy for a large number of tumours, and there is considerable interest in finding approaches that might further increase the efficacy of radiotherapy. The use of radiation leads to the generation of DNA damage and, therefore, agents that can affect the sensing and repair of DNA damage may have an impact on overall radiation efficacy. The chromatin modifications as well as chromatin modifiers that have been associated with the DNA damage response will be summarized in this review. An emphasis will be placed on those processes that can be pharmacologically manipulated with currently available inhibitors. The rationale for the use of these inhibitors in combination with radiation will also be described.
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Cromatina/química , Daño del ADN/efectos de la radiación , Reparación del ADN/efectos de la radiación , ADN de Neoplasias/efectos de la radiación , Neoplasias/radioterapia , ADN de Neoplasias/genética , Inestabilidad Genómica , Histonas/metabolismo , Humanos , Estructura Molecular , Neoplasias/genética , Neoplasias/metabolismo , Radiación IonizanteRESUMEN
Hypoxia was identified as a microenvironmental component of solid tumours over 60 years ago and was immediately recognised as a potential barrier to therapy through the reliance of radiotherapy on oxygen to elicit maximal cytotoxicity. Over the last two decades both clinical and experimental studies have markedly enhanced our understanding of how hypoxia influences cellular behaviour and therapy response. Furthermore, they have confirmed early assumptions that low oxygenation status in tumours is an exploitable target in cancer therapy. Generally such approaches will be more beneficial to patients with hypoxic tumours, necessitating the use of biomarkers that reflect oxygenation status. Tissue biomarkers have shown utility in many studies. Further significant advances have been made in the non-invasive measurement of tumour hypoxia with positron emission tomography, magnetic resonance imaging and other imaging modalities. Here, we describe the complexities of defining and measuring tumour hypoxia and highlight the therapeutic approaches to combat it.
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Resistencia a Antineoplásicos , Neoplasias/metabolismo , Neoplasias/terapia , Oxígeno/metabolismo , Animales , Antineoplásicos/farmacología , Hipoxia de la Célula , Reparación del ADN/efectos de los fármacos , Reparación del ADN/fisiología , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Imagen por Resonancia Magnética/métodos , Neoplasias/diagnóstico , Tomografía de Emisión de Positrones , Profármacos/farmacología , Transducción de Señal/fisiologíaRESUMEN
Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.
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Proteínas de Ciclo Celular/antagonistas & inhibidores , Isoxazoles/administración & dosificación , Neoplasias Pancreáticas/radioterapia , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazinas/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/efectos de la radiación , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Tolerancia a RadiaciónRESUMEN
BACKGROUND: Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is therefore essential that strategies continue to be developed to target hypoxic cancer cells. Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy. METHODS: Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE-821, in hypoxic conditions and its potential as a radiosensitiser. RESULTS: VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Consistently, ATR inhibition sensitised tumour cell lines to a range of oxygen tensions. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition. CONCLUSION: These findings suggest that ATR inhibition represents a novel strategy to target tumour cells in conditions relevant to pathophysiology and enhance the efficacy of radiotherapy.
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Proteínas de Ciclo Celular/antagonistas & inhibidores , Hipoxia de la Célula/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Tolerancia a Radiación/efectos de los fármacos , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Daño del ADN , Replicación del ADN/efectos de los fármacos , Células HCT116 , Células HeLa , Histonas/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazinas/farmacología , Tolerancia a Radiación/genética , Radioterapia/métodos , Proteínas Represoras/genética , Transducción de Señal/efectos de los fármacos , Sulfonas/farmacología , Proteína 28 que Contiene Motivos TripartitoRESUMEN
OBJECTIVE: Vitamin D deficiency (VDD) is prevalent in HIV, and following antiretroviral therapy (ART), increased rates of lipoatrophy and metabolic abnormalities are described. We investigated the relationships between 25-hydroxyvitamin D [25(OH)D] and other metabolic parameters in a group of HIV patients with and without lipoatrophy to examine whether lipoatrophy could explain the high prevalence of VDD and metabolic abnormalities. BACKGROUND: Vitamin D receptors are expressed in adipose tissue implicating vitamin D, through paracrine/autocrine mechanism, in exerting effects on fat metabolism. HIV patients frequently suffer from VDD, and those treated with thymidine analogues frequently suffer from lipoatrophy so we investigated whether lipoatrophy could explain these associations. DESIGN AND PATIENTS: Cross-sectional study of HIV-infected male patients (n = 107; 39 with lipoatrophy) from the West Australian cohort with measurements of 25(OH)D, adiponectin, insulin, lipids and leg fat as a percentage of mass. RESULTS: Reduced 25(OH)D levels were common and significantly associated with higher serum insulin in the entire cohort (P = 0·006), but there was no difference in 25(OH)D between untreated and antiretroviral-treated patients with or without lipoatrophy. Treated patients with lipoatrophy were more likely to take thymidine analogue therapy, were older and on therapy longer than treated patients without lipoatrophy. Adiponectin levels did not correlate with 25(OH)D, but lipoatrophic-treated patients had lower levels of adiponectin compared with nonlipoatrophic-treated patients. CONCLUSIONS: Lower 25(OH)D is associated with higher serum insulin but not lipoatrophy or hypoadiponectinemia in HIV-infected patients. The association between VDD and insulin resistance is likely to be mediated by independent mechanisms.
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Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Insulina/sangre , Lipodistrofia/sangre , Vitamina D/análogos & derivados , Adulto , Estudios Transversales , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Humanos , Lipodistrofia/etiología , Masculino , Persona de Mediana Edad , Vitamina D/sangreRESUMEN
Junction-mediating and regulatory protein (JMY) is a novel p53 cofactor that regulates p53 activity during stress. JMY interacts with p300/CBP, which are ubiquitous transcriptional co-activators that interact with a variety of sequence-specific transcription factors, including hypoxia-inducible factor-1α (HIF-1α). In addition, JMY is an actin-nucleating protein, which, through its WH2 domains, stimulates cell motility. In this study, we show that JMY is upregulated during hypoxia in a HIF-1α-dependent manner. The JMY gene contains HIF-responsive elements in its promoter region and HIF-1α is recruited to its promoter during hypoxia. HIF-1α drives transcription of JMY, which accounts for its induction under hypoxia. Moreover, the enhanced cell motility and invasion that occurs during hypoxia requires JMY, as depleting JMY under hypoxic conditions causes decreased cell motility. Our results establish the interplay between JMY and HIF-1α as a new mechanism that controls cell motility under hypoxic stress.
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Hipoxia de la Célula , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Proteínas Nucleares/fisiología , Transactivadores/fisiología , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Transactivadores/genéticaRESUMEN
BACKGROUND: PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models. METHODS: The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens. RESULTS: PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours. CONCLUSION: PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials.
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Inhibidores de la Angiogénesis/uso terapéutico , Glucuronidasa/uso terapéutico , Neoplasias/tratamiento farmacológico , Saponinas/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Glucuronidasa/farmacología , Células HT29 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones SCID , Metástasis de la Neoplasia , Neoplasias/patología , Neoplasias/prevención & control , Saponinas/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial. OBJECTIVE: To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection. PATIENTS AND METHODS: Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation. RESULTS: Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups. CONCLUSIONS: Blood transfusions within the first 2 weeks post-transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies.
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Transfusión de Componentes Sanguíneos/métodos , Rechazo de Injerto/prevención & control , Trasplante de Corazón/patología , Tolerancia Inmunológica/efectos de los fármacos , Adulto , Biopsia , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/inmunología , Trasplante de Corazón-Pulmón/patología , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Resultado del TratamientoRESUMEN
Activating transcription factor 4 (ATF4) is a transcription factor induced under severe hypoxia and a component of the PERK pathway involved in the unfolded protein response (UPR), a process that protects cells from the negative consequences of endoplasmic reticulum (ER) stress. In this study, we have used small interfering RNA (siRNA) and microarray analysis to provide the first whole-genome analysis of genes regulated by ATF4 in cancer cells in response to severe and prolonged hypoxic stress. We show that ATF4 is required for ER stress and hypoxia-induced expansion of autophagy. MAP1LC3B (LC3B) is a key component of the autophagosomal membrane, and in this study we demonstrate that ATF4 facilitates autophagy through direct binding to a cyclic AMP response element binding site in the LC3B promoter, resulting in LC3B upregulation. Previously, we have shown that Bortezomib-induced ATF4 stabilization, which then upregulated LC3B expression and had a critical role in activating autophagy, protecting cells from Bortezomib-induced cell death. We also showed that severe hypoxia stabilizes ATF4. In this study, we demonstrate that severe hypoxia leads to ER stress and induces ATF4-dependent autophagy through LC3 as a survival mechanism. In summary, we show that ATF4 has a key role in the regulation of autophagy in response to ER stress and provide a direct mechanistic link between the UPR and the autophagic machinery.
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Factor de Transcripción Activador 4/fisiología , Autofagia/genética , Factor de Transcripción Activador 4/antagonistas & inhibidores , Factor de Transcripción Activador 4/genética , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Secuencia de Bases , Ácidos Borónicos/farmacología , Bortezomib , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células HeLa , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxígeno/farmacología , Pirazinas/farmacología , ARN Interferente Pequeño/farmacología , Células Tumorales Cultivadas , Respuesta de Proteína Desplegada/efectos de los fármacos , Respuesta de Proteína Desplegada/genética , Estudios de Validación como AsuntoRESUMEN
The aim of this paper is to detail the experience obtained in implementing an image-guided radiation therapy program at the Northern Sydney Cancer Centre. This required retrofitting a Varian Clinac 21EX with an on-board imager. The commissioning and quality assurance procedures, organisation of a multidisciplinary image guided radiation therapy group, and the development of clinical protocols for orthogonal kV and cone beam computed tomography implementation are described. Reassessment of the image-guided radiation therapy program has continued as new equipment and software versions were made available in the department.
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Tomografía Computarizada de Haz Cónico/métodos , Radiografía Intervencional , Radioterapia/métodos , Protocolos Clínicos , Humanos , Capacitación en Servicio , Nueva Gales del Sur , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Dosis de Radiación , Programas InformáticosRESUMEN
Heparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.