RESUMEN

PURPOSE: To develop and validate a cross-ancestry integrated risk score (caIRS) that combines a cross-ancestry polygenic risk score (caPRS) with a clinical estimator for breast cancer (BC) risk. We hypothesized that the caIRS is a better predictor of BC risk than clinical risk factors across diverse ancestry groups. METHODS: We used diverse retrospective cohort data with longitudinal follow-up to develop a caPRS and integrate it with the Tyrer-Cuzick (T-C) clinical model. We tested the association between the caIRS and BC risk in two validation cohorts including > 130,000 women. We compared model discrimination for 5-year and remaining lifetime BC risk between the caIRS and T-C and assessed how the caIRS would affect screening in the clinic. RESULTS: The caIRS outperformed T-C alone for all populations tested in both validation cohorts and contributed significantly to risk prediction beyond T-C. The area under the receiver operating characteristic curve improved from 0.57 to 0.65, and the odds ratio per standard deviation increased from 1.35 (95% CI, 1.27 to 1.43) to 1.79 (95% CI, 1.70 to 1.88) in validation cohort 1 with similar improvements observed in validation cohort 2. We observed the largest gain in positive predictive value using the caIRS in Black/African American women across both validation cohorts, with an approximately two-fold increase and an equivalent negative predictive value as the T-C. In a multivariate, age-adjusted logistic regression model including both caIRS and T-C, caIRS remained significant, indicating that caIRS provides information over T-C alone. CONCLUSION: Adding a caPRS to the T-C model improves BC risk stratification for women of multiple ancestries, which could have implications for screening recommendations and prevention.

Asunto(s)

Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/diagnóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Valor Predictivo de las Pruebas

RESUMEN

BACKGROUND: The IDEAL (Idea, Development, Evaluation, Assessment, Long-term study) framework is a scheme of investigation for innovative surgical therapeutic interventions. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a procedure based on laparoscopy to deliver intraperitoneal chemotherapy for peritoneal metastases, introduced in 2011. The aim of this article was to review literature on PIPAC and assess whether development of the technique has followed the IDEAL framework. METHODS: A search of MEDLINE and Embase was carried out to identify scientific reports on PIPAC published between January 2000 and February 2019. The studies were categorized according to the IDEAL stages. RESULTS: Eighty-six original research papers on PIPAC were identified. There were 23 stage 0, 18 stage 1, 25 stage 2a and six stage 2b studies. Protocol papers for stage 1, 2b and 3 studies, and trial registrations for stage 2a studies, were also identified. The number of centres publishing reports and the number of publications has increased each year. Overall, there has been progression through the IDEAL stages; however, about 60 per cent of clinical reports published in 2018 were stage 1 Idea-type studies. CONCLUSION: Since its introduction, studies investigating PIPAC have progressed in line with the IDEAL framework. However, the majority of studies reported recently were stage 0 and 1 studies.

---

ANTECEDENTES: El marco conceptual IDEAL (Idea, Desarrollo, Exploración, Evaluación y Estudio a largo plazo) es un esquema de investigación para intervenciones quirúrgicas innovadoras. La quimioterapia intraperitoneal presurizada con aerosol (Pressurised Intraperitoneal Aerosol Chemotherapy, PIPAC) es un procedimiento introducido en 2011 y basado en la laparoscopia para administrar quimioterapia intraperitoneal en las metástasis peritoneales. El objetivo de este manuscrito era revisar la literatura sobre PIPAC y evaluar si el desarrollo de la técnica se ha hecho siguiendo el marco IDEAL. MÉTODOS: Se realizó una búsqueda en Medline y Embase para identificar publicaciones científicas sobre PIPAC aparecidas entre enero de 2000 y febrero de 2019. Los estudios se clasificaron según las etapas IDEAL. RESULTADOS: Se identificaron 86 trabajos de investigación originales sobre PIPAC. Hubo 23 estudios de la etapa 0, 18 de la etapa 1, 25 de la etapa 2a y 6 de la etapa 2b. También se identificaron protocolos para estudios de las etapas 1, 2b y 3, así como registros de ensayos para estudios de la etapa 2a. El número de centros que publican trabajos y el número de publicaciones ha aumentado cada año. En general, ha habido una progresión a través de las etapas IDEAL; sin embargo, aproximadamente el 60% de los informes clínicos publicados en 2018 fueron estudios tipo "Idea" de etapa 1. CONCLUSIÓN: Desde su introducción, los estudios que investigan PIPAC han progresado en la línea del marco IDEAL. Sin embargo, la mayoría de los estudios publicados recientemente fueron estudios de las etapas 0 y 1.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Peritoneales/tratamiento farmacológico , Aerosoles , Terapia Combinada , Humanos , Laparoscopía , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/cirugía , Presión , Resultado del Tratamiento

RESUMEN

Chytridiomycosis is an emerging infectious disease of amphibians caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), which has led to devastating declines in amphibian populations worldwide. Current theory predicts that Bd infections are maintained through both reproduction on the host's skin and reinfection from sources outside of the host. To investigate the importance of external reinfection on pathogen burden, we infected captive-bred individuals of the highly susceptible Panamanian Golden Frog, Atelopus glyphus, and wild-caught glass frogs, Espadarana prosoblepon, with Bd. We housed the animals in one of three treatments: individually, in heterospecific pairs, and in conspecific pairs. For 8 weeks, we measured the Bd load and shedding rate of all frogs. We found that Atelopus had high rates of increase in both Bd load and shedding rate, but pathogen growth rates did not differ among treatments. The infection intensity of Espadarana co-housed with Atelopus was indistinguishable from those housed singly and those in conspecific pairs, despite being exposed to a large external source of Bd zoospores. Our results indicate that Bd load in both species is driven by pathogen replication within an individual, with reinfection from outside the host contributing little to the amplification of host fungal load.

Asunto(s)

Anuros/microbiología , Quitridiomicetos/crecimiento & desarrollo , Quitridiomicetos/patogenicidad , Micosis/veterinaria , Crianza de Animales Domésticos , Animales , Micosis/epidemiología , Micosis/transmisión , Panamá/epidemiología

RESUMEN

Introduction Pan-speciality consensus guidance advocates mandatory emergency general surgery (EGS) training modules for specialist registrars (StRs). This pilot study evaluated the impact of EGS modules aimed at StRs over 1 year. Methods Eleven StRs were allocated a focused 4-week EGS module, in addition to the standard 1:12 on-call duty rota, in a tertiary surgical centre. Primary outcome measures included the number of indicative emergency operations and validated Procedure Based Assessments (PBAs) performed, both during the EGS module and over the training year. Results StRs performed a median of 11 (range 5-15) laparotomies during the EGS module versus 31 (range 9-49) over the whole training year. StRs attended 43.7% of available laparotomies during the module (range 24.1-63.7%). EGS modules provided more than one-third of the total emergency laparotomy experience, and a quarter of the emergency colectomy, appendicectomy and Hartmann's procedure experience. There were no differences in EGS module-related outcomes between junior and senior StRs. Significantly more PBAs related to laparotomy and segmental colectomy were completed during EGS modules than the on-call duty rota, at 32% versus 14% (p<0.001) and 48% versus 22% (p=0.019), respectively. Performance levels were maintained following module completion. Conclusions These findings provide an important baseline when considering future modular EGS training.

Asunto(s)

Medicina de Emergencia/educación , Cirugía General/educación , Internado y Residencia/métodos , Servicios Médicos de Urgencia/estadística & datos numéricos , Humanos , Internado y Residencia/organización & administración , Internado y Residencia/estadística & datos numéricos , Laparotomía/estadística & datos numéricos , Proyectos Piloto

RESUMEN

Pathogens vary in virulence and rates of transmission because of many differences in the host, the pathogen, and their environment. The amphibian chytrid fungus, Batrachochytrium dendrobatidis (Bd), affects amphibian hosts differently, causing extinction and population declines in some species but having limited effects on others. Phenotypic differences in zoospore production rates among Bd lineages likely contribute to some of the variation observed among host responses, although no studies have quantified the viability of zoospores shed from live animals. We compared host survivorship, infection intensity, shedding rates, and zoospore viability between 2 species of endangered tropical frogs, Hylomantis lemur and Atelopus zeteki, when exposed to a highly virulent lineage of Bd (JEL 423). We applied a dye to zoospores 30 to 60 min following animal soaks, to estimate shedding rate and proportion of live zoospores shed by different species. The average infection intensity for A. zeteki was nearly 17 times higher (31,455 ± 10,103 zoospore genomic equivalents [ZGEs]) than that of H. lemur (1832 ± 1086 ZGEs), and A. zeteki died earlier than H. lemur. The proportion of viable zoospores was ~80% in both species throughout the experiment, although A. zeteki produced many more zoospores, suggesting it may play a disproportionate role in spreading disease in communities where it occurs, because the large number of viable zoospores they produce might increase infection in other species where they are reintroduced.

Asunto(s)

Quitridiomicetos/fisiología , Micosis/veterinaria , Ranidae/microbiología , Esporas Fúngicas/fisiología , Animales , Quitridiomicetos/patogenicidad , Micosis/microbiología , Virulencia

RESUMEN

Stable isotope analysis has provided insights into the trophic ecology of a wide diversity of animals. Knowledge about isotopic incorporation rates and isotopic discrimination between the consumer and its diet for different tissue types is essential for interpreting stable isotope data, but these parameters remain understudied in many animal taxa and particularly in aquatic invertebrates. We performed a 292-day diet shift experiment on 92 individuals of the predatory mantis shrimp, Neogonodactylus bredini, to quantify carbon and nitrogen incorporation rates and isotope discrimination factors in muscle and hemolymph tissues. Average isotopic discrimination factors between mantis shrimp muscle and the new diet were 3.0 ± 0.6 ‰ and 0.9 ± 0.3 ‰ for carbon and nitrogen, respectively, which is contrary to what is seen in many other animals (e.g. C and N discrimination is generally 0-1 ‰ and 3-4 ‰, respectively). Surprisingly, the average residence time of nitrogen in hemolymph (28.9 ± 8.3 days) was over 8 times longer than that of carbon (3.4 ± 1.4 days). In muscle, the average residence times of carbon and nitrogen were of the same magnitude (89.3 ± 44.4 and 72.8 ± 18.8 days, respectively). We compared the mantis shrimps' incorporation rates, along with rates from four other invertebrate taxa from the literature, to those predicted by an allometric equation relating carbon incorporation rate to body mass that was developed for teleost fishes and sharks. The rate of carbon incorporation into muscle was consistent with rates predicted by this equation. Our findings provide new insight into isotopic discrimination factors and incorporation rates in invertebrates with the former showing a different trend than what is commonly observed in other animals.

Asunto(s)

Crustáceos/metabolismo , Hemolinfa/metabolismo , Modelos Estadísticos , Músculos/metabolismo , Animales , Isótopos de Carbono/metabolismo , Crustáceos/crecimiento & desarrollo , Peces/metabolismo , Cadena Alimentaria , Hemolinfa/química , Músculos/química , Isótopos de Nitrógeno/metabolismo , Conducta Predatoria/fisiología

Asunto(s)

Adenocarcinoma/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Adenocarcinoma/patología , Animales , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología , Frotis Vaginal/métodos

RESUMEN

The disease chytridiomycosis is responsible for declines and extirpations of amphibians worldwide. Chytridiomycosis is caused by a fungal pathogen (Batrachochytrium dendrobatidis) that infects amphibian skin. Although we have a basic understanding of the pathophysiology from laboratory experiments, many mechanistic details remain unresolved and it is unknown if disease development is similar in wild amphibian populations. To gain a better understanding of chytridiomycosis pathophysiology in wild amphibian populations, we collected blood biochemistry measurements during an outbreak in mountain yellow-legged frogs (Rana muscosa) in the Sierra Nevada Mountains of California. We found that pathogen load is associated with disruptions in fluid and electrolyte balance, yet is not associated with fluctuations acid-base balance. These findings enhance our knowledge of the pathophysiology of this disease and indicate that disease development is consistent across multiple species and in both laboratory and natural conditions. We recommend integrating an understanding of chytridiomycosis pathophysiology with mitigation practices to improve amphibian conservation.

Asunto(s)

Quitridiomicetos , Dermatomicosis/epidemiología , Dermatomicosis/fisiopatología , Dermatomicosis/veterinaria , Brotes de Enfermedades/veterinaria , Ranidae/microbiología , Animales , Análisis Químico de la Sangre/veterinaria , California/epidemiología , Dermatomicosis/sangre , Análisis de Componente Principal , Ranidae/sangre , Ranidae/fisiología , Equilibrio Hidroelectrolítico/fisiología

RESUMEN

Advanced ovarian cancer may extend into the spleen, and even the pancreatic tail, in which a splenectomy associated with distal pancreatectomy is crucial for optimal cytoreduction. A new linear stapler preloaded with tissue reinforcement is currently introduced. We herein report the first three cases of successful application of this device for distal pancreatectomy performed during cytoreductive surgery for ovarian cancer.

Asunto(s)

Neoplasias Ováricas/cirugía , Pancreatectomía/instrumentación , Engrapadoras Quirúrgicas , Adulto , Diseño de Equipo , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Esplenectomía

RESUMEN

The disease chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), has caused dramatic amphibian population declines and extinctions in Australia, Central and North America, and Europe. Bd is associated with >200 species extinctions of amphibians, but not all species that become infected are susceptible to the disease. Specifically, Bd has rapidly emerged in some areas of the world, such as in Australia, USA, and throughout Central and South America, causing population and species collapse. The mechanism behind the rapid global emergence of the disease is poorly understood, in part due to an incomplete picture of the global distribution of Bd. At present, there is a considerable amount of geographic bias in survey effort for Bd, with Asia being the most neglected continent. To date, Bd surveys have been published for few Asian countries, and infected amphibians have been reported only from Indonesia, South Korea, China and Japan. Thus far, there have been no substantiated reports of enigmatic or suspected disease-caused population declines of the kind that has been attributed to Bd in other areas. In order to gain a more detailed picture of the distribution of Bd in Asia, we undertook a widespread, opportunistic survey of over 3,000 amphibians for Bd throughout Asia and adjoining Papua New Guinea. Survey sites spanned 15 countries, approximately 36° latitude, 111° longitude, and over 2000 m in elevation. Bd prevalence was very low throughout our survey area (2.35% overall) and infected animals were not clumped as would be expected in epizootic events. This suggests that Bd is either newly emerging in Asia, endemic at low prevalence, or that some other ecological factor is preventing Bd from fully invading Asian amphibians. The current observed pattern in Asia differs from that in many other parts of the world.

Asunto(s)

Anfibios/microbiología , Quitridiomicetos/fisiología , Enfermedades Transmisibles/epidemiología , Micosis/epidemiología , Animales , Asia/epidemiología , Geografía , Modelos Biológicos , Especificidad de la Especie

RESUMEN

In nature, individual hosts often encounter multiple pathogens simultaneously, which can lead to additive, antagonistic, or synergistic effects on hosts. Synergistic effects on infection prevalence or severity could greatly affect host populations. However, ecologists and managers often overlook the influence of pathogen combinations on hosts. This is especially true in amphibian conservation, even though multiple pathogens coexist within amphibian populations, and several pathogens have been implicated in amphibian population declines and extinctions. Using an amphibian host, Pseudacris regilla (Pacific treefrog), we experimentally investigated interactive effects among three pathogens: the trematode Ribeiroia sp. (hereafter, Ribeiroia), the fungus Batrachochytrium dendrobatidis (hereafter, BD), and the water mold Achlya flagellata. We detected no effects of A. flagellata, but did find effects of Ribeiroia and BD that varied depending on context. Low doses of Ribeiroia caused relatively few malformations, while higher Ribeiroia doses caused numerous deformities dominated by missing and reduced limbs and limb elements. Exposure to low doses of BD accelerated larval host development, despite there being no detectable BD infections, while exposure to higher BD doses caused infection but did not alter developmental rate. Hosts exposed to both Ribeiroia and BD exhibited the highest mortality, although overall evidence of interactive effects of multiple pathogens was limited. We suggest further research on the influence of multi-pathogen assemblages on amphibians, particularly under a variety of ecological conditions and with a wider diversity of hosts and pathogens.

Asunto(s)

Achlya/fisiología , Anuros/microbiología , Quitridiomicetos/fisiología , Interacciones Huésped-Patógeno , Trematodos/fisiología , Animales , Anuros/crecimiento & desarrollo , Anuros/parasitología , Anomalías Congénitas/microbiología , Anomalías Congénitas/parasitología , Larva/crecimiento & desarrollo , Larva/microbiología , Larva/parasitología , Metamorfosis Biológica , Micosis/microbiología , Micosis/veterinaria , Infecciones por Trematodos/microbiología , Infecciones por Trematodos/parasitología , Infecciones por Trematodos/veterinaria

RESUMEN

Epidemiological theory generally suggests that pathogens will not cause host extinctions because the pathogen should fade out when the host population is driven below some threshold density. An emerging infectious disease, chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd) is directly linked to the recent extinction or serious decline of hundreds of amphibian species. Despite continued spread of this pathogen into uninfected areas, the dynamics of the host-pathogen interaction remain unknown. We use fine-scale spatiotemporal data to describe (i) the invasion and spread of Bd through three lake basins, each containing multiple populations of the mountain yellow-legged frog, and (ii) the accompanying host-pathogen dynamics. Despite intensive sampling, Bd was not detected on frogs in study basins until just before epidemics began. Following Bd arrival in a basin, the disease spread to neighboring populations at approximately 700 m/yr in a wave-like pattern until all populations were infected. Within a population, infection prevalence rapidly reached 100% and infection intensity on individual frogs increased in parallel. Frog mass mortality began only when infection intensity reached a critical threshold and repeatedly led to extinction of populations. Our results indicate that the high growth rate and virulence of Bd allow the near-simultaneous infection and buildup of high infection intensities in all host individuals; subsequent host population crashes therefore occur before Bd is limited by density-dependent factors. Preventing infection intensities in host populations from reaching this threshold could provide an effective strategy to avoid the extinction of susceptible amphibian species in the wild.

Asunto(s)

Quitridiomicetos/patogenicidad , Micosis/epidemiología , Micosis/microbiología , Ranidae/microbiología , Animales , California/epidemiología , Dinámica Poblacional , Virulencia

RESUMEN

BACKGROUND: Complete hydatidiform mole (CHM) is a high-risk pregnancy for gestational trophoblastic neoplasia (GTN). Patients with CHM have a 10-30% chance of trophoblastic sequelae. CHM includes androgenic homozygous (monospermic) and androgenic heterozygous (dispermic) moles. It is controversial whether the risk of GTN is higher with heterozygous than with homozygous CHM. A prospective cohort study was conducted to assess risk of GTN in homozygous and heterozygous CHM using short tandem repeat (STR) polymorphisms, and a meta-analysis of previous reports. METHODS: Twenty-eight consecutive molar pregnancies were evacuated and followed by regular hCG measurements to detect GTN. Persistent GTN was diagnosed according to the International Federation of Gynecology and Obstetrics 2000 system. Cytogenesis of the mole was determined by STR polymorphisms of molar tissue and parental blood. A meta-analysis of the GTN rate from previous reports was conducted using Mantel-Haenszel methods. RESULTS: Of 28 molar pregnancies, 24 were homozygous and three were heterozygous CHM. The remaining mole was diandric triploidy (a partial hydatidiform mole). Of the 24 homozygous CHMs, six (25%) cases developed GTN and received chemotherapy. Meanwhile, all three cases (100%) of heterozygous mole developed GTN and needed chemotherapy. The GTN risk was higher in heterozygous (P = 0.029, Fisher's exact test) than homozygous moles. A systematic review revealed only five previous reports (with more than 15 cytogenetically diagnosed cases), and the pooled relative risk of persistent GTN for heterozygous mole was not significant (odds ratio, 2.0; 95% confidence interval, 0.98-4.07). CONCLUSIONS: Heterozygous CHM had a higher risk for GTN than homozygous CHM.

Asunto(s)

Mola Hidatiforme/genética , Neoplasias Uterinas/genética , Adulto , Gonadotropina Coriónica/sangre , Estudios de Cohortes , Femenino , Heterocigoto , Homocigoto , Humanos , Mola Hidatiforme/sangre , Mola Hidatiforme/clasificación , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Embarazo , Estudios Prospectivos , Factores de Riesgo , Neoplasias Uterinas/sangre , Adulto Joven

RESUMEN

BACKGROUND: The current study examined the clinical usefulness of YKL-40 in detection and prognosis of uterine cervical cancer. PATIENTS AND METHODS: Serum levels of YKL-40, cancer antigen 125 (CA 125), carbohydrate antigen 19-9 (CA19-9), and squamous cell carcinoma (SCC) antigen were determined by enzyme-linked immunosorbent assay in women with benign gynecologic disease (n=24), cervical malignancy (SCC, n=104; adenocarcinoma, n=37), and age-matched healthy controls (n=45). Immunohistochemical analysis for local YKL-40 expression was carried out on 28 adenocarcinomas. RESULTS: Receiver operating characteristic curve analysis showed that YKL-40 [area under the curve (AUC)=0.882] was significantly better at discriminating adenocarcinoma from healthy control than SCC antigen, CA 125, and CA19-9. For SCC, YKL-40 (AUC=0.898) carried out similarly to SCC antigen and was better than CA 125 and CA19-9. Using a cut-off YKL-40 value of 92.2 ng/ml, sensitivity of YKL-40 in stage I adenocarcinoma (68%) was higher than that of the other three markers (11%-21%). Tumor-associated macrophages showed immunoreactivity for YKL-40 in 2 of 28 adenocarcinoma tissue samples, but adenocarcinoma cells themselves were nonimmunoreactive in all samples. Multivariate Cox regression analysis revealed that elevated pretreatment YKL-40 levels predicted unfavorable prognosis, independent of International Federation of Gynecology and Obstetrics stage and age at diagnosis. CONCLUSIONS: Pretreatment serum YKL-40 level is a possible prognosticator of cervical adenocarcinoma.

Asunto(s)

Adenocarcinoma/diagnóstico , Biomarcadores de Tumor/sangre , Glicoproteínas/sangre , Neoplasias del Cuello Uterino/diagnóstico , Adenocarcinoma/sangre , Adenocarcinoma/metabolismo , Adipoquinas , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Estudios de Casos y Controles , Proteína 1 Similar a Quitinasa-3 , Femenino , Glicoproteínas/metabolismo , Glicoproteínas/normas , Humanos , Lectinas , Persona de Mediana Edad , Pronóstico , Valores de Referencia , Sensibilidad y Especificidad , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/metabolismo

RESUMEN

Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition.

Asunto(s)

Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Predisposición Genética a la Enfermedad , Glicoproteínas de Membrana/genética , Proteínas del Tejido Nervioso/genética , Piracetam/análogos & derivados , Adulto , Estudios de Cohortes , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/genética , Femenino , Variación Genética , Genotipo , Hipocampo/patología , Humanos , Irlanda , Levetiracetam , Masculino , Piracetam/uso terapéutico , Polimorfismo Genético/genética , Vesículas Sinápticas/genética , Reino Unido

RESUMEN

The aim of this study was to assess acute toxicities of concurrent low-dose daily cisplatin and extended-field radiation therapy (EFRT) for carcinoma of the uterine cervix. Fifteen women with cervical cancer who were treated with concurrent daily low-dose cisplatin and EFRT were analyzed. Daily cisplatin dose was fixed to 8 mg/m(2), which was determined in the preceding phase I study using pelvic radiotherapy. Twelve patients underwent either combined external beam radiation therapy and intracavitary brachytherapy or external beam radiation therapy alone. Three other patients were treated with adjuvant chemoradiotherapy after surgery. A total dose of EFRT ranged from 40 to 45 Gy, with an additional boost to the gross tumor volume up to 50.4-55 Gy. A median total dose of cisplatin during entire radiation therapy course was 224 mg/m(2) (range, 200-240 mg/m(2)). In 14 of 15 patients (93%), daily cisplatin could be delivered continuously as planned without any modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Grade 3 thrombocytopenia was observed in three patients. Grade 2 or worse anemia was observed in 12. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Although moderate to severe hematologic toxicities are common, this study suggests that concurrent low-dose daily cisplatin and EFRT are feasible. A cumulative cisplatin dose of greater than 200 mg/m(2) during radiation therapy could be achieved by using daily cisplatin dose of 8 mg/m(2).

Asunto(s)

Antineoplásicos/uso terapéutico , Braquiterapia , Cisplatino/uso terapéutico , Neoplasias del Cuello Uterino/terapia , Adenocarcinoma/terapia , Adulto , Carcinoma de Células Escamosas/terapia , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Radioterapia Adyuvante , Medición de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/cirugía

Asunto(s)

Enfermedades Inflamatorias del Intestino/genética , Receptores de Esteroides/genética , Frecuencia de los Genes , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Receptor X de Pregnano

RESUMEN

BCL-6 is a transcription factor essential for germinal centre B-cell development. The BCL-6 gene is involved in diffuse large-cell lymphoma and overexpressed in other types of non-Hodgkin's lymphoma and in high-grade breast cancer. BCL-6 is a transcriptional repressor whose N-terminal POZ domain mediates protein-protein interactions to exert its effects. Reasoning that disruption of POZ domain-mediated interactions may be an effective route to antagonizing the effects of BCL-6 in lymphoma, we screened a library for peptide aptamers that specifically bind to BCL-6 POZ and not the POZ domains of related proteins and describe here the first of these reagents, Apt48. Apt48 binds BCL-6 POZ in a manner distinct from the transcriptional corepressor SMRT, yet was found to prevent BCL-6-mediated repression of a luciferase reporter gene. Apt48 also reproduced several previously validated effects of BCL-6 inhibition. Notably, expression of the differentiation markers CD69, Blimp-1 and cyclin D2 was increased in B-cell lines when Apt48 was expressed. We also show that expression of Apt48 restores cytokine-mediated growth arrest to BCL-6 overexpressing cells. Thus, we have identified a peptide aptamer that affects a function of BCL-6 that is required to prevent differentiation of proliferating B cells.

Asunto(s)

Aptámeros de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-bcl-6/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Western Blotting , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Diferenciación Celular , Supervivencia Celular , Técnicas Químicas Combinatorias , Ciclina D2 , Ciclinas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Inmunoprecipitación , Lectinas Tipo C , Co-Represor 2 de Receptor Nuclear , Osteosarcoma/metabolismo , Osteosarcoma/patología , Biblioteca de Péptidos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Represoras/genética , Saccharomyces cerevisiae , Factores de Transcripción/metabolismo , Transcripción Genética , Activación Transcripcional , Células Tumorales Cultivadas , Técnicas del Sistema de Dos Híbridos

RESUMEN

BACKGROUND: The tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 (SNS1/PN3) is expressed by nociceptors and may play a role in pain states. METHODS: Using specific antibodies for immunohistochemistry, we studied Nav1.8 immunoreactivity in human dental pulp in relation to the neuronal marker neurofilament. Human tooth pulp was extracted from teeth harvested from a total of twenty-two patients (fourteen without dental pain, eight patients with dental pain). RESULTS: Fibres immunoreactive for Nav1.8, were significantly increased on image analysis in the painful group: median (range) Nav1.8 to Neurofilament % area ratio, non-painful 0.059 (0.006-0.24), painful 0.265 (0.13-0.5), P = 0.0019. CONCLUSION: Nav1.8 sodium channels may thus represent a therapeutic target in trigeminal nerve pain states.