236 research outputs found
Singular measures and convolution operators
We show that in the study of certain convolution operators, functions can be
replaced by measures without changing the size of the constants appearing in
weak type (1,1) inequalities. As an application, we prove that the best
constants for the centered Hardy-Littlewood maximal operator associated to
parallelotopes do not decrease with the dimension.Comment: 8 page
Methotrexate Pharmacokinetics and Survival in Osteosarcomat
The aim of this study was to analyze the relationship between
exposure to high-dose methotrexate (HDMTX) and tumor response in terms of
survival in children with osteosarcoma. PROCEDURE: This study included 44
patients (479 courses) who received a median dose of 5.92 g/m2 of MTX
(interquartile range (IQR) 2.37 g/m2) in a 4-hr infusion. The mean area under the
concentration-time curve (AUC) estimated by parametric methods (non-parametric
expectation maximization, NPEM), and the mean concentration at the end of the
infusion were considered to be the exposure parameters. Tumor response was
recorded as disease-free survival (DFS), overall survival (OS), and histologic
tumor response. The relationship between MTX exposure and survival parameters was
analyzed by Cox regression. RESULTS: The group of 11 patients who were the least
exposed to MTX (AUC <2,400 micromol/L hr) presented a high DFS, probably due to
the shorter interval of time between MTX courses that led to a higher dose
density. In patients with AUC >2,400 micromol/L hr, an increase in the AUC was
related to an increase in the DFS. Significant differences were observed in the
DFS between patients whose mean AUC was below or above 4,000 micromol/L hr
(P=0.024), such that 4,000 micromol/L hr was considered as the minimum AUC to be
aimed at for future patients. CONCLUSIONS: Dose density seems to be an important
factor in osteosarcoma response, but this must be confirmed in further studies.
In order to improve the response to osteosarcoma in children, it is recommended
that the dose of MTX to be increased such as to obtain an AUC higher than 4,000
micromol/L hr
Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites
Purpose: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring.
Methods: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion.
Results: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug.
Conclusions: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases
Sox9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin
The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9- dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.published_or_final_versio
Some inequalities on generalized entropies
We give several inequalities on generalized entropies involving Tsallis
entropies, using some inequalities obtained by improvements of Young's
inequality. We also give a generalized Han's inequality.Comment: 15 page
Noticias de Bahía Academia
El Vivero de la ECCD. Las Amenazadas Tortugas de Cerro Paloma, Isabel. El Daño de los Chivos al Volcán Alcedo. Las Colecciones del Museo de la ECCD. Chivos en Pinta, Otra Vez? Existe un Guadalupe River en Galápagos? Avistamiento de un Tirano del Este. Tomar Palabras del Pasado. ¡Es Scalesia Atractyloides! El Beagle, Bote de Investigación de la ECCD. Alcedo al Día. Exposición de Arte a Beneficio de Alcedo. Nueva Construcción. Actividad Geológica? Ciencia de Alta Tecnología. Mas Noticias Sobre Pinta. Primer Registro de la Garza Verde (Butorides Viriscens) en las Islas Galápagos. Un Vuelo sobre los Volcanes del Norte de Isabela
WWOX P47T partial loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12
WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice brains revealed signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. Cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions of WW domain LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation, and severe cerebellar dysfunction. Our results show significant pathobiological effects and potential mechanisms through which WWOX partial LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool to understand the role of WWOX in common neurodegenerative conditions in which this gene has been identified as a novel risk factor.Fil: Hussain, Tabish. University of Texas; Estados UnidosFil: Sanchez, Kevin. University of Texas at Austin; Estados UnidosFil: Crayton, Jennifer. University of Texas; Estados UnidosFil: Saha, Dhurjhoti. University of Texas; Estados UnidosFil: Jeter, Collene. University of Texas; Estados UnidosFil: Lu, Yue. University of Texas; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Seo, Ryan. Baylor College of Medicine; Estados UnidosFil: Noebels, Jeffrey L.. Baylor College of Medicine; Estados UnidosFil: Fonken, Laura. University of Texas at Austin; Estados UnidosFil: Aldaz, C. Marcelo. University of Texas; Estados Unido
Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma
Background: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant
chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified
FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other
tumors, but scarce data is available in pancreatic cancer.
Methods: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included
in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil
(5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated.
Results: By exploratory univariate analyses, a significantly longer progression-free survival was observed
for patients with either 5-FU area under the curve (AUC) above 28 mcgh/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability
after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC 28 mcgh/mL [HR ¼ 0.189, 95% CI 0.073e0.486, p ¼ 0.001].
Conclusions: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might
improve survival outcomes in patients with pancreatic ductal adenocarcinoma
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