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1.
Plant Mol Biol ; 112(4-5): 279-291, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37326800

RESUMEN

A long-held goal of synthetic biology has been the transfer of a bacterial nitrogen-fixation pathway into plants to reduce the use of chemical fertiliser on crops such as rice, wheat and maize. There are three classes of bacterial nitrogenase, named after their metal requirements, containing either a MoFe-, VFe- or FeFe-cofactor, that converts N2 gas to ammonia. Relative to the Mo-nitrogenase the Fe-nitrogenase is not as efficient for catalysis but has less complex genetic and metallocluster requirements, features that may be preferable for engineering into crops. Here we report the successful targeting of bacterial Fe-nitrogenase proteins, AnfD, AnfK, AnfG and AnfH, to plant mitochondria. When expressed as a single protein AnfD was mostly insoluble in plant mitochondria, but coexpression of AnfD with AnfK improved its solubility. Using affinity-based purification of mitochondrially expressed AnfK or AnfG we were able to demonstrate a strong interaction of AnfD with AnfK and a weaker interaction of AnfG with AnfDK. This work establishes that the structural components of the Fe-nitrogenase can be engineered into plant mitochondria and form a complex, which will be a requirement for function. This report outlines the first use of Fe-nitrogenase proteins within a plant as a preliminary step towards engineering an alternative nitrogenase into crops.


Asunto(s)
Azotobacter vinelandii , Nitrogenasa , Nitrogenasa/genética , Nitrogenasa/metabolismo , Azotobacter vinelandii/genética , Azotobacter vinelandii/metabolismo , Hierro , Fijación del Nitrógeno , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo
2.
Ann Oncol ; 34(2): 173-185, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36414192

RESUMEN

BACKGROUND: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival. PATIENTS AND METHODS: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed. RESULTS: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population. CONCLUSION: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Nivolumab/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Ipilimumab/efectos adversos , Neoplasias Pulmonares/patología , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
3.
N Z Vet J ; 70(1): 55-62, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34346835

RESUMEN

CASE HISTORY: A 1-year-old German Shepherd dog presented for delayed onset of a traumatic, dorsal diaphragmatic hernia of the pars lumborum. CLINICAL FINDINGS AND TREATMENT: Herniorrhaphy via a ventral midline celiotomy (with and without a paracostal extension) were unsuccessful and the hernia recurred. The hernia was successfully repaired using a single lateral paracostal surgical approach. This approach provided excellent exposure and should be considered for dorsal pars lumborum diaphragmatic hernia repairs. DIAGNOSIS: Dorsal diaphragmatic hernia of the pars lumborum. CLINICAL RELEVANCE: Whilst uncommon, tears to the dorsal aspect of the diaphragm should be considered as well as the more common radial or circumferential pars costalis tears. Pre-operative computed tomographic imaging can identify the exact location of the hernia in order to allow the best surgical approach to be determined. A lateral paracostal approach should be considered as an alternative to a ventral midline celiotomy with or without paracostal extension for repair of dorsal diaphragmatic hernias affecting the pars lumborum, as it provides excellent exposure. A single lateral paracostal approach has not been reported previously for diaphragmatic hernia repair in dogs.


Asunto(s)
Enfermedades de los Perros , Hernia Diafragmática , Animales , Enfermedades de los Perros/diagnóstico por imagen , Enfermedades de los Perros/cirugía , Perros , Hernia Diafragmática/cirugía , Hernia Diafragmática/veterinaria , Herniorrafia/veterinaria
4.
Ann Oncol ; 31(5): 641-649, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32169310

RESUMEN

BACKGROUND: Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference. PATIENTS AND METHODS: We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls. RESULTS: In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER+) tumours, but no effect found for estrogen-negative (ER-) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97-1.04; P = 0.98). CONCLUSION: Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.


Asunto(s)
Neoplasias de la Mama , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Análisis de la Aleatorización Mendeliana , Factores de Riesgo
5.
Ann Oncol ; 30(6): 983-989, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31089709

RESUMEN

BACKGROUND: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods. PATIENTS AND METHODS: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method. RESULTS: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP. CONCLUSIONS: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.


Asunto(s)
Neoplasias de la Próstata/sangre , Proteínas de Secreción Prostática/sangre , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Estudios de Seguimiento , Humanos , Masculino , Análisis de la Aleatorización Mendeliana/métodos , Persona de Mediana Edad , Estado Nutricional , Pronóstico , Estudios Prospectivos , Factores de Riesgo
7.
Ir Med J ; 111(6): 773, 2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-30520278

RESUMEN

Scombrotoxic poisoning results from the improper handling and refrigeration of fish containing naturally occurring histidine. Scombroid fish species such as tuna, mackerel and swordfish contain histidine, which is converted to histamine when inadequately chilled. European legislation states that scombroid fish species should be tested for the presence of histamine and mean values should be <100mg/kg1. The authors report an outbreak of scombrotoxic fish poisoning in 12 individuals following ingestion of tuna. Symptoms occurred rapidly and included flushing, headache, palpitations and diarrhoea. Fortunately, symptoms were short lived and self-limiting except in one individual, who required anti-histamine medication. Adequate refrigeration practices are crucial in preventing scombrotoxic food poisoning.

8.
Ann Oncol ; 28(2): 270-277, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28426106

RESUMEN

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Afatinib , Anciano , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Femenino , Gefitinib , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Modelos de Riesgos Proporcionales , Quinazolinas/farmacología , Resultado del Tratamiento
9.
J Eur Acad Dermatol Venereol ; 31(6): 978-985, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28045204

RESUMEN

BACKGROUND: Recent studies report an increased risk of non-melanoma skin cancer (NMSC) in immunosuppressed patients with inflammatory bowel disease (IBD). Concurrently, paediatric IBD incidence is rising, with more patients now exposed to immunomodulators from a younger age. OBJECTIVES: To investigate NMSC incidence and to examine the risk associated with immunomodulators in the development of NMSC in patients with IBD. METHODS: This was a retrospective single-centre cohort study. Patients with IBD attending a tertiary adult hospital from 1994 to 2013 were included. Skin cancer incidence was compared with population data from the National Cancer Registry of Ireland (NCRI) to calculate standardized incidence ratio (SIR). Logistic regression was utilized for risk factor analysis. RESULTS: Two thousand and fifty-three patients with IBD were studied. The SIR for NMSC in patients with IBD taking immunomodulators overall was 1.8 (95% CI: 1.0-2.7) with age-specific rates significantly elevated across certain age categories. Exposure to thiopurines (OR: 5.26, 95% CI: 2.15-12.93, P < 0.001) and in particular thiopurines and/or tumour necrosis factor alpha (TNF-α) inhibitors (OR: 6.45, 95% CI: 2.69-15.95, P < 0.001) was significantly associated with NMSC. The majority (82%) of those exposed to a TNF-α inhibitor also had thiopurine exposure. CONCLUSIONS: Compliance with skin cancer preventative measures should be highlighted to all patients with IBD. There should be a low threshold for dermatology referral for immunosuppressed patients, particularly those with a history of exposure to dual immunomodulators from a young age.


Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Enfermedades Inflamatorias del Intestino/complicaciones , Melanoma/epidemiología , Adulto , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Melanoma/complicaciones , Estudios Retrospectivos
10.
Ann Oncol ; 27(3): 423-9, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26768165

RESUMEN

BACKGROUND: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. METHODS: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. RESULTS: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0-18.2] with dacomitinib and 9.6 months (95% CI 7.4-12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458-1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6-41.5) with dacomitinib versus 23.2 months (95% CI 16.0-31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431-1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. CONCLUSIONS: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). CLINICAL TRIALS NUMBER: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinonas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Receptores ErbB/genética , Clorhidrato de Erlotinib/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Quinazolinonas/efectos adversos
11.
Ann Oncol ; 27(11): 2103-2110, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27601237

RESUMEN

BACKGROUND: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. PATIENTS AND METHODS: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. RESULTS: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. CONCLUSIONS: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/administración & dosificación , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adulto , Afatinib , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , China , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/efectos adversos , República de Corea
12.
Ann Oncol ; 26(8): 1734-40, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25939894

RESUMEN

BACKGROUND: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. RESULTS: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvß3 and αvß5 expression was neither a predictive nor a prognostic indicator. CONCLUSIONS: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT00842712.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Cetuximab/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Receptores ErbB/metabolismo , Femenino , Humanos , Integrina alfaVbeta3/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Vitronectina/metabolismo , Venenos de Serpiente/administración & dosificación , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina , Gemcitabina
13.
Nanotechnology ; 26(8): 085204, 2015 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-25656461

RESUMEN

The charge distribution and potential profile of p-n-junctions in thin semiconductor nanowires (NWs) were analyzed. The characteristics of screening in one-dimensional systems result in a specific profile with large electric field at the boundary between the n- and p- regions, and long tails with a logarithmic drop in the potential and charge density. As a result of these tails, the junction properties depend sensitively on the geometry of external contacts and its capacity has an anomalously large value and frequency dispersion. In the presence of an external voltage, electrons and holes in the NWs can not be described by constant quasi-Fermi levels, due to small values of the average electric field, mobility, and lifetime of carriers. Thus, instead of the classical Sah-Noice-Shockley theory, the junction current-voltage characteristic was described by an alternative theory suitable for fast generation-recombination and slow diffusion-drift processes. For the non-uniform electric field in the junction, this theory predicts the forward branch of the characteristic to have a non-ideality factor η several times larger than the values 1 < η < 2 from classical theory. Such values of η have been experimentally observed by a number of researchers, as well as in the present work.

14.
Ann Oncol ; 25(9): 1681-1690, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24718890

RESUMEN

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patología , Técnicas de Diagnóstico Molecular/métodos , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética
15.
Neuroendocrinology ; 99(1): 7-17, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24356581

RESUMEN

The KNDy neuropeptides, kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn), have been implicated in regulating pulsatile luteinising hormone (LH) secretion. Studies of the interactions between KNDy signalling systems, however, are currently few. Although the stimulatory effect of kisspeptin and the inhibitory effect of Dyn on the gonadotropin-releasing hormone pulse generator are widely accepted, the effects of NKB in rodents are variable and sometimes controversial. Literature describing increased LH secretion in response to NKB receptor agonism predominates and is in line with human physiology, as well as the pathophysiology of pubertal failure associated with disruption of NKB signalling. However, the robust suppression of the LH pulse, induced by the same treatment under hypoestrogenic conditions, may hold clues as to the mechanisms of reproductive inhibition under pathological conditions. This review discusses the recent evidence for this paradox and outlines a revised working model incorporating the mechanisms by which KNDy neuropeptides modulate the reproductive axis.


Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Hormona Luteinizante/metabolismo , Neuroquinina B/metabolismo , Sistema Hipófiso-Suprarrenal/fisiología , Reproducción/fisiología , Animales , Núcleo Arqueado del Hipotálamo/fisiología , Dinorfinas/metabolismo , Humanos , Kisspeptinas/metabolismo , Masculino , Ratones , Neuroendocrinología , Ratas , Transducción de Señal
16.
Anim Genet ; 45(3): 427-38, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24673416

RESUMEN

The ruminant developmental transition from late foetus to lamb is associated with marked changes in skeletal muscle structure and function that reflect programming for new physiological demands following birth. To determine whether epigenetic changes are involved in this transition, we investigated the genomic architecture of the chromatin modification, histone 3 lysine 27 trimethylation (H3K27me3), which typically regulates early life developmental processes; however, its role in later life processes is unclear. Chromatin immunoprecipitation coupled with next-generation sequencing was used to map H3K27me3 nucleosomes in ovine longissimus lumborum skeletal muscle at 100 days of gestation and 12 weeks post-partum. In both states, H3K27me3 modification was associated with genes, transcription start sites and CpG islands and with transcriptional silencing. The H3K27me3 peaks consisted of two major categories, promoter specific and regional, with the latter the dominant feature. Genes encoding homeobox transcription factors regulating early life development and genes involved in neural functions, particularly gated ion channels, were strongly modified by H3K27me3. Gene promoters differentially modified by H3K27me3 in the foetus and lamb were enriched for gated ion channels, which may reflect changes in neuromuscular function. However, most modified genes showed no changes, indicating that H3K27me3 does not have a large role in late muscle maturation. Notably, promyogenic transcription factors were strongly modified with H3K27me3 but showed no differences between the late gestation foetus and lamb, likely reflecting their lack of involvement in the myofibre fusion process occurring in this transition. H3K27me3 is a major architectural feature of the epigenetic landscape of ruminant skeletal muscle, and it comments on gene transcription and gene function in the context of late skeletal muscle development.


Asunto(s)
Metilación de ADN , Histonas/metabolismo , Lisina/metabolismo , Ovinos/genética , Animales , Cromatina/metabolismo , Epigénesis Genética , Femenino , Inmunoprecipitación/veterinaria , Masculino , Datos de Secuencia Molecular , Músculo Esquelético/embriología , Músculo Esquelético/crecimiento & desarrollo , Nucleosomas/genética , Nucleosomas/metabolismo , Análisis de Secuencia de ADN/veterinaria , Ovinos/embriología , Ovinos/crecimiento & desarrollo , Ovinos/metabolismo
17.
Anaesthesia ; 69(3): 245-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24447324

RESUMEN

We compared the force of extraction for peripheral nerve catheters under three different situations in a porcine model using untunnelled, tunnelled and double-tunnelled catheters. Following insertion of the catheter into the porcine model, the catheters were either left untunnelled or a single or double tunnel was created for the catheter. The force required to displace the catheter by one centimetre was then measured in each of the three groups. The mean (SD) force required for displacement of the catheter was 0.23 (0.06) N for the untunnelled catheters, 1.16 (0.51) N for the single-tunnelled catheters, and 4.00 (1.70) N for the double-tunnelled catheters (p < 0.0001). Tunnelling a peripheral nerve catheter leads to a significant increase in the force required for dislodgement. This is increased further by introducing a second tunnel.


Asunto(s)
Catéteres , Remoción de Dispositivos , Nervios Periféricos , Animales , Catéteres de Permanencia , Tamaño de la Muestra , Porcinos
18.
Ir Med J ; 107(7): 201-4, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25226713

RESUMEN

Epidermal growth factor receptor (EGFR) gene mutations determine the treatment and prognosis in lung adenocarcinoma. Exon 19 and exon 21 (L858R) deletions represent the most common recognised mutations detected. To date, no figures regarding the prevalence of EGFR mutations in the Irish population have been published. The prevalence of EGFR mutations was retrospectively analysed for all patient samples tested since the introduction of EGFR testing routinely (Mar to Dec 2012) in a single Irish institute. The presence of 41 known treatment linked EGFR mutations in exons 18, 19, 20 and 21 of the EGFR gene was tested in 209 Irish patients. Resection, core biopsy or FNA samples were analysed using a commercially available CE-IVD marked multiplex real-time PCR assay. Samples were included from patients of curative and palliative treatment intent likely to harbour an EGFR mutation.


Asunto(s)
Receptores ErbB/genética , Mutación , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Incidencia , Neoplasias Pulmonares/genética , Masculino , Reacción en Cadena de la Polimerasa , Prevalencia , Estudios Retrospectivos , Investigación Biomédica Traslacional
19.
Clin Exp Metastasis ; 41(3): 219-228, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38416302

RESUMEN

High rates of mortality in non-small cell lung cancer lung cancer is due to inherent and acquired resistance to systemic therapies and subsequent metastatic burden. Metastasis is supported by suppression of the immune system at secondary organs and within the circulation. Modulation of the immune system is now being exploited as a therapeutic target with immune checkpoint inhibitors. The tracking of therapeutic efficacy in a real-time can be achieved with liquid biopsy, and evaluation of circulating tumour cells and the associated immune cells. A stable liquid biopsy biomarker for non-small cell lung cancer lung cancer has yet to be approved for clinical use. We performed a cross-sectional single-site study, and collected liquid biopsies from patients diagnosed with early, locally advanced, or metastatic lung cancer, undergoing surgery, or systemic therapy (chemotherapy/checkpoint inhibitors). Evaluation of overall circulating tumour cell counts, or cluster counts did not correlate with patient outcome. Interestingly, the numbers of Pan cytokeratin positive circulating tumour cells engulfed by tumour associated monocytes correlated strongly with patient outcome independent of circulating tumour cell counts and the use of checkpoint inhibitors. We suggest that Pan cytokeratin staining within monocytes is an important indicator of tumour-associated inflammation post-therapy and an effective biomarker with strong prognostic capability for patient outcome.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Queratinas , Neoplasias Pulmonares , Monocitos , Células Neoplásicas Circulantes , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Masculino , Femenino , Queratinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Monocitos/metabolismo , Anciano , Persona de Mediana Edad , Estudios Transversales , Biomarcadores de Tumor/metabolismo , Pronóstico , Biopsia Líquida/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano de 80 o más Años , Adulto
20.
ESMO Open ; 8(6): 102065, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37988950

RESUMEN

BACKGROUND: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression. PATIENTS AND METHODS: Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint. RESULTS: At 19.5 months' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings. CONCLUSIONS: CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Nivolumab/efectos adversos , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/tratamiento farmacológico
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