Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, ...epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm
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, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.
Filarial nematodes, including Brugia malayi, the causative agent of lymphatic filariasis, undergo molting in both arthropod and mammalian hosts to complete their life cycles. An understanding of how ...these parasites cross developmental checkpoints may reveal potential targets for intervention. Pharmacological evidence suggests that ecdysteroids play a role in parasitic nematode molting and fertility although their specific function remains unknown. In insects, ecdysone triggers molting through the activation of the ecdysone receptor: a heterodimer of EcR (ecdysone receptor) and USP (Ultraspiracle).
We report the cloning and characterization of a B. malayi EcR homologue (Bma-EcR). Bma-EcR dimerizes with insect and nematode USP/RXRs and binds to DNA encoding a canonical ecdysone response element (EcRE). In support of the existence of an active ecdysone receptor in Brugia we also cloned a Brugia rxr (retinoid X receptor) homolog (Bma-RXR) and demonstrate that Bma-EcR and Bma-RXR interact to form an active heterodimer using a mammalian two-hybrid activation assay. The Bma-EcR ligand-binding domain (LBD) exhibits ligand-dependent transactivation via a GAL4 fusion protein combined with a chimeric RXR in mammalian cells treated with Ponasterone-A or a synthetic ecdysone agonist. Furthermore, we demonstrate specific up-regulation of reporter gene activity in transgenic B. malayi embryos transfected with a luciferase construct controlled by an EcRE engineered in a B. malayi promoter, in the presence of 20-hydroxy-ecdysone.
Our study identifies and characterizes the two components (Bma-EcR and Bma-RXR) necessary for constituting a functional ecdysteroid receptor in B. malayi. Importantly, the ligand binding domain of BmaEcR is shown to be capable of responding to ecdysteroid ligands, and conversely, ecdysteroids can activate transcription of genes downstream of an EcRE in live B. malayi embryos. These results together confirm that an ecdysone signaling system operates in B. malayi and strongly suggest that Bma-EcR plays a central role in it. Furthermore, our study proposes that existing compounds targeting the insect ecdysone signaling pathway should be considered as potential pharmacological agents against filarial parasites.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastoma is the most common primary brain tumour. Despite advances in treatment, its prognosis remains dismal, with a mean survival time of about 14 months. Many articles have addressed direct ...costs, those associated with the diagnosis and treatment of the disease. Indirect costs, those associated with loss of productivity due to the disease, have seldom been described.
We conducted a retrospective study in patients diagnosed with glioblastoma at Hospital Universitario Donostia between January 1, 2010 and December 31, 2013. We collected demographics, data regarding the treatment received, and survival times. We calculated the indirect costs with the human capital approach, adjusting the mean salaries of comparable individuals by sex and age and obtaining mortality data for the general population from the Spanish National Statistics Institute. Past salaries were updated to 2015 euros according to the annual inflation rate and we applied a discount of 3.5% compounded yearly to future salaries.
We reviewed the records of 99 patients: 46 women (mean age 63.53) and 53 men (mean age 59.94); 29 patients underwent a biopsy and the remaining 70 underwent excisional surgery. Mean survival was 18.092 months for the whole series. The total indirect cost for the series was €11 080 762 (2015). Mean indirect cost per patient was €111 926 (2015).
Although glioblastoma is a relatively uncommon type of tumour, accounting for only 4% of all cancers, its poor prognosis and potential sequelae generate disproportionately large morbidity and mortality rates which translate to high indirect costs. Clinicians should be aware of the societal impact of glioblastoma and indirect costs should be taken into account when cost effectiveness studies are performed to better illustrate the overall consequences of this disease.
Resumen Introducción El glioblastoma es el tumor cerebral más frecuente. A pesar de los avances en su tratamiento, el pronóstico sigue siendo pobre, con una supervivencia media en torno a los 14 ...meses. Los costes directos, aquellos asociados al diagnóstico y el tratamiento de la enfermedad, han sido descritos ampliamente. Los costes indirectos, aquellos derivados de la pérdida de productividad debido a la enfermedad, han sido descritos en escasas ocasiones. Material y método Realizamos un estudio retrospectivo, incluyendo a los pacientes diagnosticados entre el 1 de enero del 2010 y el 31 de diciembre del 2013 de glioblastoma en el Hospital Universitario Donostia. Recogimos datos demográficos, relativos al tratamiento ofertado y la supervivencia. Calculamos los costes indirectos a través del método del capital humano, obteniendo datos de sujetos comparables según sexo y edad, y de mortalidad de la población general a través del Instituto Nacional de Estadística. Los salarios pasados fueron actualizados a euros de 2015 según la tasa de inflación interanual y los salarios futuros fueron descontados en un 3,5% anual en forma de interés compuesto. Resultados Revisamos a 99 pacientes, 46 mujeres (edad media 63,53 años) y 53 hombres (edad media 59,94 años). En 29 pacientes se realizó una biopsia y en los 70 restantes se realizó una cirugía resectiva. La supervivencia global media fue de 18,092 meses. Los costes indirectos totales fueron de 11.080.762 € (2015). El coste indirecto medio por paciente fue de 111.926 € (2015). Discusión A pesar de que el glioblastoma es un tipo relativamente poco frecuente de tumor, que supone el 4% de todos los tipos de cáncer, su mal pronóstico y sus posibles secuelas generan una mortalidad y morbilidad desproporcionadamente altas. Esto se traduce en unos costes indirectos muy elevados. El clínico debe ser consciente del impacto del glioblastoma en la sociedad y los costes indirectos deben ser tenidos en cuenta en los estudios de coste-efectividad para conocer las consecuencias globales de esta enfermedad.
Glioblastoma is the most common primary brain tumour. Despite advances in treatment, its prognosis remains dismal, with a mean survival time of about 14 months. Many articles have addressed direct ...costs, those associated with the diagnosis and treatment of the disease. Indirect costs, those associated with loss of productivity due to the disease, have seldom been described.
We conducted a retrospective study in patients diagnosed with glioblastoma at Hospital Universitario Donostia between January 1, 2010 and December 31, 2013. We collected demographics, data regarding the treatment received, and survival times. We calculated the indirect costs with the human capital approach, adjusting the mean salaries of comparable individuals by sex and age and obtaining mortality data for the general population from the Spanish National Statistics Institute. Past salaries were updated to 2015 euros according to the annual inflation rate and we applied a discount of 3.5% compounded yearly to future salaries.
We reviewed the records of 99 patients: 46 women (mean age 63.53) and 53 men (mean age 59.94); 29 patients underwent a biopsy and the remaining 70 underwent excisional surgery. Mean survival was 18.092 months for the whole series. The total indirect cost for the series was €11080762 (2015). Mean indirect cost per patient was €111926 (2015).
Although glioblastoma is a relatively uncommon type of tumour, accounting for only 4% of all cancers, its poor prognosis and potential sequelae generate disproportionately large morbidity and mortality rates which translate to high indirect costs. Clinicians should be aware of the societal impact of glioblastoma and indirect costs should be taken into account when cost effectiveness studies are performed to better illustrate the overall consequences of this disease.
El glioblastoma es el tumor cerebral más frecuente. A pesar de los avances en su tratamiento, el pronóstico sigue siendo pobre, con una supervivencia media en torno a los 14 meses. Los costes directos, aquellos asociados al diagnóstico y el tratamiento de la enfermedad, han sido descritos ampliamente. Los costes indirectos, aquellos derivados de la pérdida de productividad debido a la enfermedad, han sido descritos en escasas ocasiones.
Realizamos un estudio retrospectivo, incluyendo a los pacientes diagnosticados entre el 1 de enero del 2010 y el 31 de diciembre del 2013 de glioblastoma en el Hospital Universitario Donostia. Recogimos datos demográficos, relativos al tratamiento ofertado y la supervivencia. Calculamos los costes indirectos a través del método del capital humano, obteniendo datos de sujetos comparables según sexo y edad, y de mortalidad de la población general a través del Instituto Nacional de Estadística. Los salarios pasados fueron actualizados a euros de 2015 según la tasa de inflación interanual y los salarios futuros fueron descontados en un 3,5% anual en forma de interés compuesto.
Revisamos a 99 pacientes, 46 mujeres (edad media 63,53 años) y 53 hombres (edad media 59,94 años). En 29 pacientes se realizó una biopsia y en los 70 restantes se realizó una cirugía resectiva. La supervivencia global media fue de 18,092 meses. Los costes indirectos totales fueron de 11.080.762 € (2015). El coste indirecto medio por paciente fue de 111.926 € (2015).
A pesar de que el glioblastoma es un tipo relativamente poco frecuente de tumor, que supone el 4% de todos los tipos de cáncer, su mal pronóstico y sus posibles secuelas generan una mortalidad y morbilidad desproporcionadamente altas. Esto se traduce en unos costes indirectos muy elevados. El clínico debe ser consciente del impacto del glioblastoma en la sociedad y los costes indirectos deben ser tenidos en cuenta en los estudios de coste-efectividad para conocer las consecuencias globales de esta enfermedad.
To evaluate the association of host genetics with changes in limb or trunk fat in a group of antiretroviral therapy (ART)-naive HIV-infected patients prospectively followed up according to the ...initiation and the type of ART.
Fifty single nucleotide polymorphisms (SNPs) in 26 genes, associated with obesity, insulin resistance, lipid metabolism or lipodystrophy in previously published genetic studies, were assessed in ART-naive HIV-infected Caucasian patients divided into three groups: 24 (27%) did not start ART, 29 (32.6%) received zidovudine or stavudine and 36 (40.4%) received neither zidovudine nor stavudine in their initial regimen. Patients underwent body fat measurements (using dual-energy X-ray absorptiometry) at baseline and Month 12. A multivariate model using backward stepwise elimination was used to assess the influence of SNPs and baseline levels of non-genetic covariates on changes in limb or trunk fat.
The baseline characteristics were: 73% men, 17% coinfected with hepatitis C virus and/or hepatitis B virus, median age 37 years, median CD4+ T cell count 228/mm(3), median HIV-RNA 5.2 log copies/mL, median plasma glucose 85 mg/dL, median plasma insulin 9.1 IU/mL, median limb fat 5.6 kg and median trunk fat 7.0 kg. There were no baseline differences among the three groups except for the CD4+ T cell count. The decrease in limb fat was greater in the no-ART group relative to the other two groups (P < 0.05). The multivariate model showed associations of rs1801278 in IRS1 (P = 0.029, OR = 0.13), baseline viral load (P = 0.006; OR = 4.453) and baseline glucose levels (P = 0.008, OR = 0.926) with loss of limb fat, and rs2228671 in LDLR (P = 0.012, OR = 0.108), rs405509 in APOE (P = 0.048, OR = 0.205), baseline viral load (P = 0.005, OR = 0.186) and baseline CD4+ T cell count (P = 0.01, OR = 1.008) with gain of trunk fat.
Specific polymorphisms in IRS1 (limb fat loss) and LDLR and APOE (trunk fat gain) were identified as independent markers of fat changes irrespective of the initiation of ART and the type of ART and deserve further validation.
Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, ...we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P < 0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL, and COXIV were significantly down-regulated in the EFV arm compared to the LPV/r arm (P < 0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms and between CEBP/A or COXIV change and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial LIPOTAR study registered at ClinicalTrials.gov under identifier NCT00759070.).
Penicillium purpurogenum produces several enzymes active in xylan hydrolysis, of there, the acetyl xylan esterase (AXE) activity secreted by the fungus has now been studied. The amount of activity ...obtained in the culture is related to the degree of acetylation of the carbon source used, the best being chemically acetylated xylan. AXE was concentrated from culture supernatants by ultrafiltration and (NH4)2SO4 precipitation and fractionated by gel filtration in Bio-Gel P-300. Two peaks of activity (AXE I and AXE II) were obtained. These two enzymes were further purified separately to homogeneity by chromatography in CM-Sephadex C-50 and chromatofocusing. AXE I (M(r) 48,000) has a pl of 7.5, while AXE II (M(r) 23,000) has a pl of 7.8. Optimal enzyme activity was at pH 5.3 and 50 degrees C for AXE I and pH 6.0 and 60 degrees C for AXE II. Both enzymes are active towards several acetylated substrates. Antisera against the two enzymes do not cross-react, and the N-terminal sequences of AXE I and II do not show similarities. These results suggest that AXE I and AXE II are the products of different genes.
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