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Papers by Alejandra Nieto

Lancet Oncology, 2009

Results from clinical trials have established sunitinib as a standard of care for first-line trea... more Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897. As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1-25). Reasons for discontinuation included lack of efficacy (n=1168 [27%]) and adverse events (n=362 [8%]). The most common treatment-related adverse events were diarrhoea (n=1936 [44%]) and fatigue (n=1606 [37%]). The most common grade 3-4 adverse events were fatigue (n=344 [8%]) and thrombocytopenia (n=338 [8%]) with incidences of grade 3-4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]) and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival was 18.4 months (17.4-19.2). In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials. Pfizer Inc.

Mexico is a country whose development process has been traditionally characterised by a substanti... more Mexico is a country whose development process has been traditionally characterised by a substantial unbalanced performance of its regions. Since the early 1980’s it carried out an intense liberalisation and export promotion programme representative of a new national development stratagem. This paper looks at the spatial patterns of Mexican manufacturing at the same time as the shifts after the trade liberalisations are particularly weighed up. Data on manufacturing Gross Domestic Product by state is employed for an examination of shares, agglomeration indices and densities. The data reveals a long-run dispersion tendency, the changes however are small. Although the ‘‘largest’’ geographic dispersion happened after the generalised liberalisation programme and after the entry into force of the North America Free Trade Agreement relocation was already in progress in the 1970’s. States in the north were the initial beneficiaries of the spatial decentralisation of manufacturing but states in the so called Bajío region have had the major upward changes more recently. There is no evidence of a significant change in a dual regional structure. The argument about cumulative causation and the advantages of initial conditions is pertinent for the case of Mexico City. Moreover a multi-agglomerate pattern within the core is consolidating.

Archives of Internal Medicine, 2007

REVIEWER COMMENTS. Previous studies have shown that ICSs are more effective asthma-controller med... more REVIEWER COMMENTS. Previous studies have shown that ICSs are more effective asthma-controller medications compared with montelukast in children older than 6 years. Although this study failed to show statistical significance in the primary outcome, it provides data supporting certain treatment benefits of ICSs in children younger than 6 years (257 of 395 children were Ͻ5 years old). Compared with previous studies, these children had milder asthma, with only 12% having taken ICSs before enrollment.

Acta Biomaterialia, 2009

A modified two-step sol-gel route using silicon ethoxide (TEOS) has been used to synthesize amorp... more A modified two-step sol-gel route using silicon ethoxide (TEOS) has been used to synthesize amorphous sol-gel-derived silica, which has been successfully used as a cell encapsulation matrix for 3T3 mouse fibroblasts and CRL-2595 epithelial cells due to its non-toxicity. The sol-gel procedure comprised a first, low pH hydrolysis step, followed by a neutral condensation-gelation step. A high water-to-TEOS ratio and the addition of d-glucose as a porogen and source of nutrients were chosen to minimize silica dissolution and improve the biocompatibility of the process. Indeed, the cell integrity in the encapsulation process was preserved by alcohol removal from the starting solution. Cells were then added in a buffered medium, causing rapid gelation and entrapment of the cells within a randomly structured siloxane matrix in the shape of a monolith, which was maintained in the wet state. MTT and alamarBlue assays were used to check the cytotoxicity of the silica gels and the viability of entrapped cells at initial times in contact with silica. To improve cell attachment, cell clumping experiments - where groups of cells were formed - were designed, rendering improved viability. The obtained materials are therefore excellent candidates for designing tissue-culture scaffolds and implantable bioreactors for biomedical applications.

Journal of Biomedical Materials Research Part A, 2009

Biphasic calcium phosphate, a mixture of hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), ... more Biphasic calcium phosphate, a mixture of hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), has been successfully used as an excellent bone graft substitute because of the HA capacity for direct interaction with bone and the β-TCP resorption properties. Agarose has been recently mixtured with ceramics as natural biodegradable binder to increase the biomaterial flexibility facilitating its placement into the bone defect. In this study, the behavior of L929 fibroblasts and Saos-2 osteoblasts cultured on hydroxyapatite-βTCP/agarose disks has been evaluated. Both cell types adhere and proliferate on the biomaterial surface maintaining their characteristic morphology. Transitory changes on cell cycle, size, and complexity are observed. The biomaterial induces apoptosis in Saos-2 osteoblasts but not in fibroblasts. A transitory stimulation of fibroblast mitochondrial activity is observed. This effect remains in osteoblasts after 9 days of culture showing a higher sensitivity of this cell type. However, the intracellular reactive oxygen species content and the lactate dehydrogenase release of Saos-2 osteoblasts indicate that hydroxyapatite-βTCP/agarose does not induce oxidative stress in this cell type and confirm the integrity of the osteoblast plasma membrane. These results underline the good biocompatibility of hydroxyapatite-βTCP/agarose disks and its potential utility for bone substitution and repair. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009

Journal of Biomedical Materials Research Part A, 2008

The bacterial adherence onto different multifunctional silica-based bioceramics has been evaluate... more The bacterial adherence onto different multifunctional silica-based bioceramics has been evaluated. Staphylococcus aureus and Staphylococcus epidermidis were chosen, as they cause the majority of the implant-related infections in this field. Two SiO2 mesoporous materials (MCM-41, SBA-15), an ordered SiO2-CaO-P2O5 mesoporous glass (OMG), and a biphasic magnetic bioceramic (BMB), were incubated with S. aureus and S. epidermidis for 90 min, and subsequently sonicated to quantify the number of adhered bacteria on each material. It was found that S. aureus and S. epidermidis (108 CFU/mL) adhered significantly less to BMB samples when compared to MCM-41, SBA-15, or OMG. However, when the material pores accessible for bacteria in each material were taken into account, the lowest bacterial adherence was found in MCM-41, and the highest in SBA-15. The results show that bacterial adherence is higher on mesoporous bioceramics, although this higher microbial attachment is mainly due to the intergranular porosity and grain size morphology rather than to the mesoporous structure. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009

Microporous and Mesoporous Materials, 2008

It is of great interest the design of materials able to adjust the drug amount to the clinical ne... more It is of great interest the design of materials able to adjust the drug amount to the clinical needs, in such a way that the dosage can be controlled as adsorption and release are modulated. The organic modification of the surface of silica-based ordered mesoporous ...

Langmuir, 2010

The fundamental mechanisms of biologically active molecule adsorption and release from ordered me... more The fundamental mechanisms of biologically active molecule adsorption and release from ordered mesoporous silica are discussed in terms of the variation of surface electrochemistry after functionalization. Specifically, ordered mesoporous SBA-15 has been grafted with aminopropyl, etilenediamine, phosphatoethyl, propyl methacrylate, and carboxylic acid groups at different degrees of functionalization. To test the molecular adsorption and release features, three molecules of clinical interest have been selected, namely, antiresorptive zoledronic acid, amino acid L-tryptophan, and protein bovine serum albumin. Molecular loading and delivery aspects have been studied by emphasizing the host-guest interactions, which determine the adsorption and release behavior. It has been found that careful control of surface electrochemistry by functionalization determines the bioactive molecule adsorption whereas the release can be mainly thought of as a diffusion matter dependent on the surface area and molecule size. This enhanced approach opens up new ways to optimize molecule loading for specific clinical needs.

Acta Biomaterialia, 2011

There is an acknowledged need for shaping 3-D scaffolds with adequate porosity and mechanical pro... more There is an acknowledged need for shaping 3-D scaffolds with adequate porosity and mechanical properties for biomedical applications. The mechanical properties under static and cyclic compressive testing of dense and designed porous architecture bioceramic scaffolds based on the biphasic calcium phosphate (BCP) systems and BCP-agarose systems have been evaluated. The dense and designed porous architecture scaffolds in BCP systems exhibited a brittle behaviour. Agarose, a biocompatible and biodegradable hydrogel, has been used to shape designed architecture ceramic-agarose scaffolds following a low-temperature shaping method. Agarose conferred toughness, ductility and a rubbery consistency for strains of up to 60% of in ceramic BCP-agarose systems. This combination of ceramic and organic matrix helps to avoid the inherent brittleness of the bioceramic and enhances the compression resistance of hydrogel. The presence of mechanical hysteresis, permanent deformation after the first cycle and recovery of the master monotonous curve indicate a Mullins-like effect such as that observed in carbon-filled rubber systems. We report this type of mechanical behaviour, the Mullins effect, for the first time in bioceramics and bioceramic-agarose systems.