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BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.
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Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Prednisona , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Proteína BRCA1/genética , Reparación del ADN por Recombinación , Resultado del Tratamiento , Proteína BRCA2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.
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Antagonistas de Receptores Androgénicos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Tiohidantoínas/administración & dosificación , Antagonistas de Receptores Androgénicos/efectos adversos , Estudios Cruzados , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Placebos/efectos adversos , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Tiohidantoínas/efectos adversos , Factores de TiempoRESUMEN
Microbial processes are critical to the function of freshwater ecosystems, yet we still do not fully understand the factors that shape freshwater microbial communities. Furthermore, freshwater ecosystems are particularly susceptible to effects of environmental change, including influx of exogenous nutrients such as nitrogen and phosphorus. To evaluate the impact of nitrogen loading on the microbial community structure of shallow freshwater lakes, water samples collected from Lake Shenandoah (Virginia, USA) were incubated with two concentrations of either ammonium, nitrate, or urea as a nitrogen source. The potential impact of these nitrogen compounds on the bacterial community structure was assessed via 16S rRNA amplicon sequencing. At the phylum level, the dominant taxa in Lake Shenandoah were comprised of Actinobacteria and Proteobacteria, which were not affected by exposure to the various nitrogen treatments. Overall, there was not a significant shift in the diversity of the bacterial community of Lake Shenandoah with the addition of nitrogen sources, indicating this shallow system may be constrained by other environmental factors.
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Lagos , Nitrógeno , Bacterias , Proteobacteria , ARN Ribosómico 16SRESUMEN
BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.
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Antagonistas de Andrógenos/uso terapéutico , Mutación Puntual , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Tiohidantoínas/uso terapéutico , Anciano , Anciano de 80 o más Años , ADN Tumoral Circulante/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point. PATIENTS AND METHODS: Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form. RESULTS: Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66-0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65-0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE. CONCLUSION: In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.
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Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/secundario , Denosumab/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Neoplasias Óseas/complicaciones , Método Doble Ciego , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.
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Adenocarcinoma/terapia , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/terapia , Neoplasias de la Próstata/terapia , Taxoides/uso terapéutico , Adenocarcinoma/patología , Antineoplásicos/uso terapéutico , Docetaxel , Humanos , Masculino , Orquiectomía , Guías de Práctica Clínica como Asunto , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/patología , Radioterapia AdyuvanteRESUMEN
BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.
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Dioxoles/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Estudios de Cohortes , Dioxoles/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Orquiectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Sarcoma/patología , Sarcoma/cirugía , Tetrahidroisoquinolinas/efectos adversos , Trabectedina , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
A radiofrequency coil based on a solenoid design was developed and integrated with a novel device for MR-guided breast interventions using a circumferential approach. The transmit/receive tapered solenoid design conforms to the shape of the pendent breast, and provides open circumferential needle access to breast tissue under rotational symmetry. Phantom and in vivo studies using a healthy volunteer demonstrated a superior uniformity using the tapered solenoid coil compared with a commercial 8-channel diagnostic imaging coil. The solenoid coil design has important advantages due to localized transmit/receive such as B(1) -homogeneity and reduced specific absorption ratio (SAR) especially at high-field strengths. Because it provides open access and a rotationally symmetric local field, the tapered solenoid design can easily be adapted for bilateral imaging and 3D MR-guided breast interventions.
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Neoplasias de la Mama/patología , Imagen por Resonancia Magnética Intervencional/instrumentación , Biopsia , Diseño de Equipo , Femenino , Humanos , Ondas de RadioRESUMEN
Transgenic mosquitoes generated by transposable elements (TEs) often poorly express transgenes owing to position effects. To avoid these effects, the ΦC31 site-directed recombination system was used to insert transgenes into a locus favourable for gene expression in Aedes aegypti. We describe phenotypes of mariner Mos1 TE and ΦC31 transgenic mosquitoes expressing the enhanced green fluorescent protein (EGFP) reporter in midguts of blood-fed females. Mosquitoes of nine TE-generated lines [estimated transformation frequency (TF): 9.3%] clearly expressed the eye-specific selection marker but only 2/9 lines robustly expressed the EGFP reporter. The piggyBac TE-generated ΦC31 docking strain, attP26, supported recombination with attB site containing donors at an estimated TF of 1.7-4.9%. Using a codon-optimized ΦC31 integrase mutant instead of the 'wild-type' enzyme did not affect TF. Site-directed recombination of line attP26 with an attB-containing donor expressing EGFP from the Ae. aegypti carboxypeptidase promoter produced one transgenic line with blood-fed females expressing the reporter in midgut tissue. Docking strain attP26 also supported robust expression of Flock House virus B2 from the Ae. aegypti polyubiquitin promoter. Our data confirm that eye-specific selection marker expression alone is not a reliable indicator for robust gene-of-interest expression in Ae. aegypti and that the ΦC31 system can ensure predictable transgene expression in this mosquito species.
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Aedes/metabolismo , Bacteriófagos , Técnicas de Transferencia de Gen , Transgenes , Animales , Elementos Transponibles de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Tracto Gastrointestinal/metabolismo , Expresión Génica , Genes Reporteros , Integrasas/metabolismo , Regiones Promotoras Genéticas , Interferencia de ARN , Recombinación Genética , Transposasas/metabolismoRESUMEN
REASONS FOR PERFORMING THE STUDY: Removal of large chip fractures of the carpal bones and the osteochondral deficits that result, have been associated with a worse prognosis than removal of small fragments in similar locations. HYPOTHESIS: Reducing the articular defects by repair of large osteochondral fragments may have advantages over removal. METHODS: Horses with osteochondral chip fractures that were of sufficient size and infrastructure to be repaired with small (2.7 mm diameter) AO/ASIF cortex screws were identified and repair effected by arthroscopically guided internal fixation. RESULTS: Thirty-three horses underwent surgery to repair 35 fractures of the dorsodistal radial carpal bone (n = 25), the dorsal margin of the radial facet of the third carpal bone (n = 9) and the intermediate facet of the distal radius (n = 1). There were no surgical complications and fractures healed satisfactorily in 26 of 28 horses and 23 horses returned to racing performance. CONCLUSION: Arthroscopically guided repair of carpal chip fractures with small diameter cortex screws is technically feasible and experiences with 33 cases suggest that this may have advantages over fragment removal in managing such cases. POTENTIAL RELEVANCE: Surgeons treating horses with large chip fractures of the carpal bones should consider arthroscopically guided internal fixation as an alternative to removal.
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Artroscopía/veterinaria , Tornillos Óseos/veterinaria , Carpo Animal/lesiones , Enfermedades de los Caballos/cirugía , Caballos/lesiones , Articulaciones/cirugía , Animales , Carpo Animal/patología , Carpo Animal/cirugía , Femenino , Enfermedades de los Caballos/patología , Articulaciones/lesiones , Articulaciones/patología , Masculino , Estudios RetrospectivosRESUMEN
REASONS FOR PERFORMING THE STUDY: A minimally invasive arthroscopic technique for removal of fractures of the lateral malleolus of the tibia is considered to be beneficial but data to this effect are required. HYPOTHESIS: Arthroscopic removal of fractures of the lateral malleolus of the tibia is technically feasible, provides a comprehensive evaluation of the tarsocrural joint and enables removal of remote comminuted fragments and disrupted short collateral ligaments. The technique is associated with low patient morbidity, requires only short periods of hospitalisation and affords a good prognosis to affected horses. METHODS: The case records of all horses that underwent arthroscopic removal of a fractured lateral malleolus of the tibia, admitted to a referral hospital, were evaluated retrospectively. Follow-up information was obtained from race records and by telephone questionnaire. RESULTS: Fractures were successfully removed arthroscopically in all cases following dissection from the short lateral collateral ligaments. Significant post operative complications occurred in only one horse. All other horses recovered well from surgery and of 22 horses with long-term follow-up, 18 returned to their previous use. CONCLUSION: Arthroscopic removal of fractures of the lateral malleolus of the tibia is technically demanding, but can be performed with minimal complications and with low patient morbidity and short periods of hospitalisation. The majority of horses are able to successfully return to work following the procedure. POTENTIAL RELEVANCE: The advantages of arthroscopic removal compared to removal via arthrotomy make this the technique of choice for treatment of fractures of the lateral malleolus of the tibia.
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Artroscopía/veterinaria , Miembro Posterior/lesiones , Enfermedades de los Caballos/cirugía , Caballos/lesiones , Fracturas de la Tibia/veterinaria , Animales , Femenino , Masculino , Fracturas de la Tibia/cirugíaRESUMEN
Heat labile opsonins (HLO) in normal rat serum to both encapsulated and unencapsulated pneumococci (a) have the same heat lability as complement (C); (b) are active at 37 degrees C but not at 0 degrees C; (c) are inactivated proportionately to hemolytic C by the addition of immune aggregates to the serum; (d) are adsorbed from serum nonspecifically by bacteria at 37 degrees C but not at 0 degrees C; (e) are Ca(++)- and/or Mg(++)-dependent in their action; and (f) are inactivated by zymosan and a purified cobra venom factor, and in the case of encapsulated pneumococci, at least, by NH(4)OH. Like other opsonins, HLO to pneumococci act primarily on the bacteria rather than on the phagocytes. Their combined properties indicate that they involve multiple components of the hemolytic C system. Since HLO are immunologically polyspecific, they presumably play a broad protective role in the early (preantibody) phase of acute bacterial infections.
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Proteínas del Sistema Complemento , Proteínas Opsoninas , Fagocitosis , Streptococcus pneumoniae/inmunología , Adsorción , Animales , Calcio/farmacología , Escherichia coli , Calor , Concentración de Iones de Hidrógeno , Cinética , Leucocitos , Magnesio/farmacología , Compuestos de Amonio Cuaternario/farmacología , Ratas , Serpientes , Streptococcus pneumoniae/efectos de los fármacos , Ponzoñas/farmacología , Zimosan/farmacologíaRESUMEN
When encapsulated type 25 pneumococci (Pn25) were opsonized with normal guinea pig serum, they consumed much more C3 than other complement (C) components. Fixation of C3 to the organisms was demonstrated by radio-labeling techniques, and its capsular localization was established by the use of monospecific anti-C3 antibody. Treatment of the serum with an appropriate dose of a purified cobra venom factor (VF) destroyed C3 and all of the opsonic activity, without appreciably affecting the other C components. Addition of purified C3 completely restored the opsonic activity of the VF-treated serum, indicating a requirement for C3. Since purified C3 alone had no opsonic activity, it was concluded that the C3 molecules had to be cleaved (to C3b) to function as opsonins. Experiments with C5-deficient mice revealed that C5 also plays a definite, but quantitatively less impressive, role in antipneumococcal defense.
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Proteínas del Sistema Complemento , Proteínas Opsoninas , Fagocitosis , Streptococcus pneumoniae/inmunología , Animales , Anticuerpos , Cobayas , Calor , Inyecciones Intraperitoneales , Isótopos de Yodo , Métodos , Ratones , Microscopía Fluorescente , Serpientes , Ponzoñas/farmacologíaRESUMEN
BACKGROUND: we conducted a multicentre Phase 1b/2 trial to evaluate the safety and efficacy of mapatumumab, a fully human agonistic monoclonal antibody to the tumour necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) in patients with relapsed non-Hodgkin's lymphoma (NHL). METHODS: forty patients with relapsed or refractory NHL were treated with either 3 or 10 mg kg(-1) mapatumumab every 21 days. In the absence of disease progression or prohibitive toxicity, patients received a maximum of six doses. RESULTS: mapatumumab was well tolerated, with no patients experiencing drug-related hepatic or other dose-limiting toxicity. Three patients with follicular lymphoma (FL) experienced clinical responses, including two with a complete response and one with a partial response. Immunohistochemistry staining of the TRAIL-R1 suggested that strong staining in tumour specimens did not appear to be a requirement for mapatumumab activity in FL. CONCLUSIONS: mapatumumab is safe and has promising clinical activity in patients with FL.
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Anticuerpos Monoclonales/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/análisis , RecurrenciaRESUMEN
REASONS FOR PERFORMING STUDY: Injury to the superficial digital flexor tendon (SDFT) is common in racing and sport horses and poor tendon regeneration leads to high reinjury rates. Autologous mesenchymal stromal cells (MSCs) are being used clinically to improve tendon regeneration but they have some practical limitations. Embryonic stem cells (ESCs) may overcome these limitations but their fate following injection into the damaged SDFT is unknown. OBJECTIVE: To inject MSCs and ESCs into distinct areas of damage in the SDFT and monitor their survival over a 3 month period. METHODS: MSCs and ESCs expressing different reporter genes were injected into separate sites of mechanically induced damage in SDFTs. Cell survival and distribution were examined post mortem after 10, 30, 60 and 90 days and host immune responses determined. RESULTS: Neither MSCs nor ESCs produced signs of cell-mediated immune response or tumour formation. ESC survival was high and numbers were maintained at a constant level over 90 days. ESCs were present at all sites of damage. In contrast, MSCs showed <5% survival at 10 days and numbers declined over the course of the experiment. MSCs were detected only at the site into which they were injected. CONCLUSIONS: ESCs survived in greater numbers than MSCs in the damaged tendon and did not induce an immune response, or form tumours at the injection sites in the 90 day time period studied. ESCs also demonstrated an ability to migrate to other areas of damage within the same tendon, whereas MSCs did not. POTENTIAL RELEVANCE: ESCs can be used allogeneically, therefore providing a possible 'off the shelf' source of cells for therapeutic use which overcomes the practical limitations of autologous MSCs. Furthermore, MSCs and ESCs have different survival rates and migration patterns in the damaged tendon, suggesting that they may produce different functional effects. This may have clinical relevance to treating tendon injuries in the horse.
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Células Madre Embrionarias/trasplante , Enfermedades de los Caballos/terapia , Trasplante de Células Madre Mesenquimatosas/veterinaria , Células Madre Mesenquimatosas/citología , Traumatismos de los Tendones/veterinaria , Animales , Células Madre Embrionarias/citología , Caballos , Traumatismos de los Tendones/terapiaRESUMEN
BACKGROUND: Slab fractures of the third carpal bone (C3) are a common injury of Thoroughbred racehorses. Results of arthroscopically guided repair have not been reported since the initial description of the technique in 1986. Additionally, fracture details and racing outcomes in a population of Thoroughbreds racing under UK jurisdiction have not previously been described. OBJECTIVES: To report the frequency distribution of C3 slab fractures and to determine the impact on racing performance following arthroscopically guided repair in a population of Thoroughbred racehorses. STUDY DESIGN: Retrospective case series. METHODS: Case records of Thoroughbred racehorses undergoing arthroscopically guided repair of C3 slab fractures at Newmarket Equine Hospital between 2006 and 2015 were retrieved. Radiographs and arthroscopic studies were reviewed. The effect of demography and fracture morphology on racing outcome was evaluated. RESULTS: C3 slab fractures occurred most commonly through the radial facet in a frontal plane (45/71 63.4%). Comminution was identified during arthroscopy in 42/71 (59.2%) fractures and occurred most frequently at the palmar margin of the fracture. Forty-one out of 65 horses (63.1%) raced at least once post-operatively. Females were less likely to return to racing compared to males (P<0.001). Horses that had raced before injury were more likely (OR 4.4, 95% CI 1.4-13.5, P = 0.01) to race after injury compared to horses that were unraced at the time of injury. After injury horses had a small but significant reduction in racing performance. MAIN LIMITATIONS: The series is a preselected population of Thoroughbred racehorses which referring veterinary surgeons considered potential candidates for surgical repair. CONCLUSION: Fracture configurations can be identified radiographically but is not a reliable predictor of comminution or other intra-articular lesions. Arthroscopy not only directs repair but also identifies and facilitates management of concurrent lesions. The results reported should assist in formulating appropriate prognoses for Thoroughbred horses racing in the UK.
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Huesos del Carpo , Fracturas Óseas/veterinaria , Enfermedades de los Caballos , Deportes , Animales , Femenino , Caballos , Masculino , Estudios Retrospectivos , Reino UnidoRESUMEN
The genetic contribution to different aspects of empathy is now established, although the exact loci are unknown. We undertook a genome-wide association study of emotional empathy (EE) as measured by emotion recognition skills in 4,780 8-year old children from the ALSPAC cohort who were genotyped and imputed to Phase 1 version 3 of the 1000 Genomes Project. We failed to find any genome-wide significant signal in either our unstratified analysis or analysis stratified according to sex. A gene-based association analysis similarly failed to find any significant loci. In contrast, our transcriptome-wide association study (TWAS) with a whole blood reference panel identified two significant loci in the unstratified analysis, residualised for the effects of age, sex and IQ. One signal was for CD93 on chromosome 20; this gene is not strongly expressed in the brain, however. The other signal was for AL118508, a non-protein coding pseudogene, which completely lies within CD93's genomic coordinates, thereby explaining its signal. Neither are obvious candidates for involvement in the brain processes that underlie emotion recognition and its developmental pathways.
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Cromosomas Humanos Par 20/genética , Emociones , Empatía/genética , Genotipo , Herencia Multifactorial , Transcriptoma , Niño , Cromosomas Humanos Par 20/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Estudios Longitudinales , MasculinoRESUMEN
BACKGROUND: This study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC). METHODS: Men with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured. RESULTS: Seventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin. CONCLUSIONS: Sunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.