Papers by alejandro sanchez
Journal of the American College of Cardiology
Journal of Clinical Oncology, 2018
Z 96) vs those with intermediate-to low GEsOH (n Z 146). HDMC was validated in the DKTK-ROG prima... more Z 96) vs those with intermediate-to low GEsOH (n Z 146). HDMC was validated in the DKTK-ROG primary cohort. Results: HDMC-predicted classes (high 53% vs low 47%) were associated with significant differences in overall survival (OS, p<0.05) in the TCGA training cohort. HDMC-based assignment (41% high vs 59% low) revealed significant correlation with OS (p<0.02), progression (p<0.002) and LR (p<0.0006) in HPV-patients of the DKTK-ROG validation cohort. HDMC remained significant on adjusted multivariate analysis for anatomical site, age, gender and T-stage for LR, progression and OS in the DKTK-ROG validation cohort (HRs 1.8-2.2, p<0.05). Conclusion: A methylation-based classifier of tumor hypoxia is successfully developed and validated to be prognostic for LR, progression and OS in HPV-HNSCC patients treated with primary RCHT.
International journal of cancer, Aug 28, 2018
Phenotypic transformation of liver sinusoidal endothelial cells is one of the most important stag... more Phenotypic transformation of liver sinusoidal endothelial cells is one of the most important stages of liver metastasis progression. The miRNA effects on liver sinusoidal endothelial cells during liver metastasis have not yet been studied. Herein, whole genome analysis of miRNA expression in these cells during colorectal liver metastasis revealed repressed expression of microRNA-20a. Importantly, downregulation of miR-20a occurs in parallel with upregulation of its known protein targets. To restore normal miR-20a levels in liver sinusoidal endothelial cells, we developed chondroitin sulfate-sorbitan ester nanoparticles conjugated with miR-20a in a delivery system that specifically targets liver sinusoidal endothelial cells. The restoration of normal mir-20a levels in these cells induced downregulation of the expression of its protein targets, and this also resulted in a reduction of in vitro LSEC migration and a reduction of in vivo activation and tumor-infiltrating capacity and abi...
Colloids and surfaces. B, Biointerfaces, Jan 12, 2015
Cationized polymers have been proposed as transfection agents for gene therapy. The present work ... more Cationized polymers have been proposed as transfection agents for gene therapy. The present work aims to improve the understanding of the potential use of different cationized proteins (atelocollagen, albumin and gelatin) as nanoparticle components and to investigate the possibility of modulating the physicochemical properties of the resulting nanoparticle carriers by selecting specific protein characteristics in an attempt to improve current ocular gene-delivery approaches. The toxicity profiles, as well as internalization and transfection efficiency, of the developed nanoparticles can be modulated by modifying the molecular weight of the selected protein and the amine used for cationization. The most promising systems are nanoparticles based on intermediate molecular weight gelatin cationized with the endogenous amine spermine, which exhibit an adequate toxicological profile, as well as effective association and protection of pDNA or siRNA molecules, thereby resulting in higher tr...
Drug Discovery Today: Disease Models, 2006
... Model, Pros, Cons, Best use of model, Refs. Invitromodels. Broth macrodilution, visual MIC, R... more ... Model, Pros, Cons, Best use of model, Refs. Invitromodels. Broth macrodilution, visual MIC, Reproducible standard, Visual end-points fail to detect large numbers of organisms, Rapid screening tool, [6]. Trailing end-points for azole drugs make clear end-points difficult to define, ...
The Journal of Urology, 2015
total and fatal pathology-confirmed RCC by BMI immediately prior to diagnosis. Models were adjust... more total and fatal pathology-confirmed RCC by BMI immediately prior to diagnosis. Models were adjusted for diabetes, hypertension, smoking, alcohol intake, NSAID use, physical activity, and parity in women. Results from the two cohorts were pooled using random effects metaanalysis. RESULTS: We confirmed 351 cases of RCC, including 105 fatal cases, in NHS, and 225 cases in HPFS, with 49 fatal cases. Compared to women with normal BMI (18.5-24.9 kg/m2) immediately prior to diagnosis, obese women (BMI30) had a non-significantly increased risk of RCC (HR 1.29, 95% CI: 0.97-1.72, p-trend¼0.04), adjusting for possible confounders. The HR for fatal RCC was similar (HR 1.30, 95% CI: 0.77-2.20, p-trend¼0.50). Obese men had a nonsignificantly increased risk of RCC (HR 1.44, 95% CI: 0.95-2.19, p-trend¼0.08), with a significantly increased risk of fatal RCC (HR 2.48, 95% CI: 1.08-5.72, p-trend¼0.16). There was no evidence of significant differences in the associations by sex. The pooled HRs for total RCC incidence were 1.21 (95% CI: 0.99-1.47) for overweight and 1.34 (95% CI: 1.05-1.69) for obese compared to normal weight, p-trend¼0.007. For fatal RCC, the pooled HRs were 1.11 (95% CI: 0.75-1.63) for overweight and 1.65 (0.95% CI: 0.90-3.04) for obese, p-trend¼0.18. CONCLUSIONS: Our results support that obesity is a risk factor for RCC incidence. Associations for fatal RCC were similar in magnitude to those for total RCC, though not statistically significant, suggesting that obesity is also adversely associated with risk of fatal RCC.
The AIDS reader, 2007
Hemophagocytic syndrome is a macrophage disorder that may develop as a result of immunological ac... more Hemophagocytic syndrome is a macrophage disorder that may develop as a result of immunological activation, such as that seen in severe infection. It has been described in persons with HIV/AIDS and in those with a variety of HIV-associated opportunistic infections, including those caused by Histoplasma capsulatum. If present, this disorder may portend a poorer prognosis. We describe an HIV-positive person in whom histoplasmosis-associated hemophagocytic syndrome was successfully treated.
Cold Spring Harbor protocols, 2010
INTRODUCTIONNew nanoparticulate blend compositions based on poly(D,L lactic-co-glycolic acid) (PL... more INTRODUCTIONNew nanoparticulate blend compositions based on poly(D,L lactic-co-glycolic acid) (PLGA) and poly(ethylene oxide) (PEO) derivatives have been designed as transmucosal gene carriers. These nanosystems benefit from the inherent biodegradability and low toxicity of their components and the mild conditions required for their preparation. In addition, specific advantages of these nanoparticles for in vivo gene delivery are (1) their adequate DNA loading capacity, (2) their ability to control the release of the encapsulated DNA for extended periods of time while preserving its delicate conformational structure as well as its biological activity, and (3) their capacity to overcome the nasal mucosa barrier and transport the associated model DNA vaccine, leading to a significant systemic immune response against the encoded protein. This protocol describes the preparation and characterization of DNA-loaded nanoparticles composed of poly(lactic acid) (PLA) and PEO and the use of these particles as transmucosal gene delivery carriers.
HIV clinical trials
In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acut... more In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. To determine clinical and immunological predictors of death after an OI. We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis j...
International journal of pharmaceutics, Jan 30, 2014
Nanoparticles based on naturally-occurring biopolymers, most of them endogenous macromolecules, w... more Nanoparticles based on naturally-occurring biopolymers, most of them endogenous macromolecules, were designed as a versatile generation of delivery platforms for delicate bioactive molecules. The design of these nanosystems was specifically based on our recent finding about the ability of endogenous polyamine spermine (SPM) to interact with anionic biopolymers (ABs) generating ionically cross-linked nanosystems. The initial first generation of these delivery platforms, based on glycosaminoglycans and other polysaccharides, showed a very high association capacity for some delicate bioactive proteins such as growth factors, but a limited capacity to associate negatively charged molecules, such as pDNA and siRNA. However, the versatility of these nanosystems in terms of composition allowed us to customise the association of active ingredients and their physicochemical characteristics. Concretely, we prepared and incorporated gelatine cationized with spermine (CGsp) to their composition...
Nature reviews. Urology, Jan 3, 2015
Changes in health-related quality of life following the diagnosis and treatment of patients with ... more Changes in health-related quality of life following the diagnosis and treatment of patients with non-muscle-invasive bladder cancer (NMIBC) remain poorly understood. A new study suggests that diagnosis and treatment of NMIBC might affect mental health as well as sexual, urinary and bowel function.
Molecular Pharmaceutics, 2014
The intrinsic ability of albumin to bind active substances in the physiological fluids has been e... more The intrinsic ability of albumin to bind active substances in the physiological fluids has been explored to endow hydrogels with improved capability to regulate drug release. To develop such biomimetic-functional hydrogels, it is critical that albumin conformation is not altered and that the protein remains retained inside the hydrogel keeping its conformational freedom, i.e., it should be not chemically cross-linked. Thus, the hydrogels were prepared with various proportions of albumin by physical cross-linking of anionic polysaccharides (gellan gum and chondroitin sulfate) with the cationic endogen polyamine spermidine under mild conditions in order to prevent albumin denaturation. Texture and swelling properties of hydrogels with various compositions were recorded, and the effect of the preparation variables was evaluated applying neurofuzzy logic tools for hydrogels prepared with and without albumin and associating the antibiotic cloxacillin. Developed hydrogel systems were extensively analyzed by means of nuclear magnetic resonance (NMR) to determine weak-to-medium and strong binding modes and the equilibrium constants of the albumin-cloxacillin association. NMR techniques were also employed to demonstrate the successful modulation of the cloxacillin release from the albumin-containing hydrogels. In vitro microbiological tests carried out with Staphylococcus aureus and Staphylococcus epidermidis confirmed the interest of the albumin-containing hydrogels as efficient platforms for cloxacillin release in its bioactive form.
Current Opinion in Pulmonary Medicine, 2007
Invasive fungal infections of the lung have been increasing due to the increase of the population... more Invasive fungal infections of the lung have been increasing due to the increase of the population most at risk. This review aims to describe some of the emerging fungal pathogens and their complex management. With the increase in immunosuppressed populations, physicians are increasingly encountering uncommon fungal pathogens that historically have been difficult to identify and treat. Many of these fungal infections present with similar clinical features and often show similar histopathological changes. Treatment options are more complex because of an increasing number of antifungals that have become available for clinical use. The correct usage of these antifungals in addressing emerging fungal infections is unclear, however. Drawing from in-vitro and in-vivo susceptibility testing and case reports, some deductions may be made for the best empirical treatment of these deadly diseases. In general, the newer triazoles (voriconazole and posiconazole) and the use of combination therapy have shown promise. Invasive fungal infections are on the increase and contribute significantly to overall mortality, particularly among transplant recipients. With the lack of well designed controlled clinical studies, physicians will need to draw from previously described cases and in-vitro susceptibility testing to optimize therapy.
Vaccine, 2014
The adjuvant properties of polyglucosamine/squalene-based nanocapsules (PG-nanocapsules) associat... more The adjuvant properties of polyglucosamine/squalene-based nanocapsules (PG-nanocapsules) associated with different subunit antigens has been previously reported. Thus, the aim of the present study was to monitor the biodistribution of PG-nanocapsules and their affinity for the draining lymph nodes after subcutaneous (s.c.) injection. The nanocapsules were efficiently radiolabeled with indium-111 (111 In) (labeling efficiency of 98%). The diameter and zeta potential values of the unlabeled nanocapsules was preserved after the radiolabeling process and only 20% of the 111 In dissociated from the nanocapsules after 48 h of incubation in serum. The radiolabeled nanocapsules and the control 111 InCl 3 in saline solution (18.5 MBq (500 Ci) in 100 L) were injected s.c. in New Zealand White rabbits. The ␥-scintigraphy imaging analysis revealed a slow clearance of the nanocapsules from the injection site and their progressive accumulation in the popliteal lymph node over time (3.8% ± 1.2 of the injected dose at 48 h). Indeed, the clearance rate of the nanocapsules from the injection site was significantly slower than that of the control (free 111 InCl 3), which rapidly drained into systemic circulation and accumulated mainly in excretion organs (i.e. kidneys and liver). In contrast, the biodistribution of nanocapsules was preferably limited to the lymphatic circulation. These results suggest that the immune potentiating effect previously observed for PG-nanocapsules is mainly due to the formation of a depot at the injection site, which was followed by a slow drainage into the lymphatic system and a prolonged retention in the lymph nodes.
Progress in Nuclear Magnetic Resonance Spectroscopy, 2014
Significant progress has been made over the last three decades in the field of NMR, a technique w... more Significant progress has been made over the last three decades in the field of NMR, a technique which has proven to have a variety of applications in many scientific disciplines, including nanotechnology. Herein we describe how NMR enables the characterization of nanosystems at different stages of their formation and modification (raw materials, bare or functionalized nanosystems), even making it possible to study in vivo nanoparticle interactions, thereby importantly contributing to nanoparticle design and subsequent optimization. Furthermore, the unique characteristics of nanosystems can open up new prospects for site-targeted, more specific contrast agents, contributing to the development of certain nuclear magnetic resonance applications such as MRI.
New England Journal of Medicine, 2011
Background Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients in... more Background Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known. Methods We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. Results A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log 10 copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], −1.8 to 8.1; P = 0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P = 0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P = 0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P = 0.38). Conclusions Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death.
Nanomedicine, 2014
Aim: To develop a new core-shell type (nanocapsules) adjuvant system composed of squalene and pol... more Aim: To develop a new core-shell type (nanocapsules) adjuvant system composed of squalene and polyglucosamine (PG) and to evaluate its immunostimulant capacity. Results: The defined PG nanocapsules exhibited the capacity to efficiently associate the selected antigens (recombinant hepatitis B surface antigen and hemagglutinin of influenza virus) onto their polymeric surface (70–75%), and the immunostimulant imiquimod within the oily core. The resulting nanovaccines, with a particle size of 200–250 nm and a positive zeta-potential (∼+60 mV), were able to significantly potentiate and modulate the immune response to the selected antigens upon intramuscular administration to mice. Their efficacy as novel adjuvants was attributed to their enhanced cell internalization and effective intracellular imiquimod/antigen delivery, together with their prolonged residence time at the injection site. Conclusion: The nanocapsules described herein have the capacity to enhance, prolong and modulate the...
Nanomedicine, 2010
Aim: To design and develop a new nanocarrier appropriately engineered for the adequate accommodat... more Aim: To design and develop a new nanocarrier appropriately engineered for the adequate accommodation of a virus-like particle, the recombinant hepatitis B surface antigen (22 nm), and intended to be used for the transmucosal delivery of the associated antigen. The nanoparticles consisted of a core blend of poly(D,L-lactide-co-glycolide) and poloxamer 188, and a hydrophilic shell of chitosan. Results: By by conveniently adapting the nanoprecipitation technique, it was possible to associate a significant amount of active antigen (44%) to the nanocarrier. The resulting nanosystems had a size of around 200 nm and positive zeta potential attributed to the association of chitosan. The nanoparticles were able to deliver the associated antigen in a controlled manner for up to 14 days without compromising its activity, as determined by ELISA. Moreover, the antigenicity of the recombinant hepatitis B surface antigen was preserved for at least 14 days, when stored as an aqueous suspension, and...
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Papers by alejandro sanchez