Current perspectives on the use of anti-VEGF drugs as adjuvant therapy in glaucoma

The approval of one of the first anti-vascular endothelial growth factor (VEGF) agents for the treatment of neovascular age-related macular degeneration one decade ago marked the beginning of a new era in the management of several sight-threatening retinal diseases. Since then, emerging evidence has demonstrated the utility of these therapies for the treatment of other ocular conditions characterized by elevated VEGF levels. In this article we review current perspectives on the use of anti-VEGF drugs as adjuvant therapy in the management of neovascular glaucoma (NVG). The use of anti-VEGFs for modifying wound healing in glaucoma filtration surgery (GFS) is also reviewed. Selected studies investigating the use of anti-VEGF agents or antimetabolites in GFS or the management of NVG have demonstrated that these agents can improve surgical outcomes. However, anti-VEGF agents have yet to demonstrate specific advantages over the more established agents commonly used today. Further studies are needed to evaluate the duration of action, dosing intervals, and toxicity profile of these treatments

Controlled delivery of tauroursodeoxycholic acid from biodegradable microspheres slows retinal degeneration and vision loss in P23H rats

Successful drug therapies for treating ocular diseases require effective concentrations of neuroprotective compounds maintained over time at the site of action. The purpose of this work was to assess the efficacy of intravitreal controlled delivery of tauroursodeoxycholic acid (TUDCA) encapsulated in poly(D, L-lactic-co-glycolic acid) (PLGA) microspheres for the treatment of the retina in a rat model of retinitis pigmentosa. PLGA microspheres (MSs) containing TUDCA were produced by the O/W emulsion-solvent evaporation technique. Particle size and morphology were assessed by light scattering and scanning electronic microscopy, respectively. Homozygous P23H line 3 rats received a treatment of intravitreal injections of TUDCA-PLGA MSs. Retinal function was assessed by electroretinography at P30, P60, P90 and P120. The density, structure and synaptic contacts of retinal neurons were analyzed using immunofluorescence and confocal microscopy at P90 and P120. TUDCA-loaded PLGA MSs were spherical, with a smooth surface. The production yield was 78%, the MSs mean particle size was 23 mu m and the drug loading resulted 12.5 +/- 0.8 mu g TUDCA/mg MSs. MSs were able to deliver the loaded active compound in a gradual and progressive manner over the 28-day in vitro release study. Scotopic electroretinografic responses showed increased ERG a- and b-wave amplitudes in TUDCA-PLGA-MSstreated eyes as compared to those injected with unloaded PLGA particles.TUDCA-PLGAMSs- treated eyes showed more photoreceptor rows than controls. The synaptic contacts of photoreceptors with bipolar and horizontal cells were also preserved in P23H rats treated with TUDCA-PLGA MSs. This work indicates that the slow and continuous delivery of TUDCA from PLGA-MSs has potential neuroprotective effects that could constitute a suitable therapy to prevent neurodegeneration and visual loss in retinitis pigmentosa

Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8+ T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-α) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8+ immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-α- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-α, which, given together, constitute a potent approach to significantly enhance the CD8+ T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions

Desarrollo e implementación de un dispositivo de adquisición y almacenamiento de sonidos para ganadería de precisión

El monitoreo preciso de las actividades alimentarias de los rumiantes (rumia y pastoreo) es un importante indicador de su salud y bienestar. Un buen seguimiento en la dieta repercute de manera directa en la calidad y cantidad de la leche y carne producidas por el animal. En este trabajo se describe el desarrollo e implementación de un dispositivo de adquisición y almacenamiento de señales para el monitoreo de actividades alimentarias en ganado bovino. Dicho dispositivo tiene por objetivo captar los sonidos producidos por los animales durante su alimentación, sin interferir en su comportamiento normal y sin intervención del operador. El sistema propuesto consta de tres módulos: i) un módulo de adquisición y limpieza del sonido producido por el animal, ii) un módulo de compresión de la señal resultante, organización y almacenamiento de los datos y iii) un módulo de administración de la energía. El sistema fue diseñado para tener una autonomía de una semana y soportar las condiciones operacionales presentes en el campo de aplicación, como son la presencia de ruidos y condiciones climáticas adversas.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Long-Term Systemic Expression of a Novel PD-1 Blocking Nanobody from an AAV Vector Provides Antitumor Activity without Toxicity

Immune checkpoint blockade using monoclonal antibodies (mAbs) able to block programmed death-1 (PD-1)/PD-L1 axis represents a promising treatment for cancer. However, it requires repetitive systemic administration of high mAbs doses, often leading to adverse effects. We generated a novel nanobody against PD-1 (Nb11) able to block PD-1/PD-L1 interaction for both mouse and human molecules. Nb11 was cloned into an adeno-associated virus (AAV) vector downstream of four different promoters (CMV, CAG, EF1α, and SFFV) and its expression was analyzed in cells from rodent (BHK) and human origin (Huh-7). Nb11 was expressed at high levels in vitro reaching 2–20 micrograms/mL with all promoters, except SFFV, which showed lower levels. Nb11 in vivo expression was evaluated in C57BL/6 mice after intravenous administration of AAV8 vectors. Nb11 serum levels increased steadily along time, reaching 1–3 microgram/mL two months post-treatment with the vector having the CAG promoter (AAV-CAG-Nb11), without evidence of toxicity. To test the antitumor potential of this vector, mice that received AAV-CAG-Nb11, or saline as control, were challenged with colon adenocarcinoma cells (MC38). AAV-CAG-Nb11 treatment prevented tumor formation in 30% of mice, significantly increasing survival. These data suggest that continuous expression of immunomodulatory nanobodies from long-term expression vectors could have antitumor effects with low toxicity

Desarrollo e implementación de un dispositivo de adquisición y almacenamiento de sonidos para ganadería de precisión

El monitoreo preciso de las actividades alimentarias de los rumiantes (rumia y pastoreo) es un importante indicador de su salud y bienestar. Un buen seguimiento en la dieta repercute de manera directa en la calidad y cantidad de la leche y carne producidas por el animal. En este trabajo se describe el desarrollo e implementación de un dispositivo de adquisición y almacenamiento de señales para el monitoreo de actividades alimentarias en ganado bovino. Dicho dispositivo tiene por objetivo captar los sonidos producidos por los animales durante su alimentación, sin interferir en su comportamiento normal y sin intervención del operador. El sistema propuesto consta de tres módulos: i) un módulo de adquisición y limpieza del sonido producido por el animal, ii) un módulo de compresión de la señal resultante, organización y almacenamiento de los datos y iii) un módulo de administración de la energía. El sistema fue diseñado para tener una autonomía de una semana y soportar las condiciones operacionales presentes en el campo de aplicación, como son la presencia de ruidos y condiciones climáticas adversas.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Novel use of plga microspheres to create an animal model of glaucoma with progressive neuroretinal degeneration

Progressive degeneration of neuroretinal tissue with maintained elevated intraocular pressure (IOP) to simulate chronic glaucoma was produced by intracameral injections of poly (lactic-co-glycolic) acid (PLGA) microspheres (Ms) in rat eyes. The right eye of 39 rats received different sizes of PLGA-Ms (2 µL suspension; 10% w/v): 14 with 38–20 µm Ms (Ms38/20 model) and 25 with 20–10 µm particles (Ms20/10 model). This novel glaucoma animal model was compared to the episcleral vein sclerosis (EPI) model (25 eyes). Injections were performed at baseline, two, four and six weeks. Clinical signs, IOP, retina and optic nerve thicknesses (using in vivo optical coherence tomography; OCT), and histological studies were performed. An IOP increment was observed in all three groups, however, the values obtained from the PLGA-Ms injection resulted lower with a better preservation of the ocular surface. In fact, the injection of Ms20/10 created a gentler, more progressive, and more sustained increase in IOP. This IOP alteration was correlated with a significant decrease in most OCT parameters and in histological ganglion-cell count for the three conditions throughout the eight-week follow-up. In all cases, progressive degeneration of the retina, retinal ganglion cells and optic nerve, simulating chronic glaucoma, was detected by OCT and corroborated by histological study. Results showed an alternative glaucoma model to the well-known episcleral vein model, which was simpler to perform, more reproducible and easier to monitor in vivo

Algoritmo para el monitoreo acústico en tiempo real de la actividad alimenticia del ganado bovino

La evaluación tanto del comportamiento de pastoreo como de la ingesta de pasturas en rumiantes es una tarea compleja que puede ser llevada a cabo adecuadamente por medio de la detección, clasificación y medición precisa de eventos de pastoreo como: chews, bites y chewbites. Es bien conocido que el monitoreo acústico es uno de los mejores métodos para cuantificar y clasificar eventos ingestivos de la actividad alimenticia de rumiantes. Sin embargo, la mayoría de los métodos de análisis son complejos y costosos computacionalmente, además de difíciles de implementar. En este trabajo presentamos y evaluamos un novedoso sistema de análisis llamado Chew-Bite Real-Time Algorithm (CBRTA) que trabaja automáticamente en tiempo real para detectar y clasificar eventos ingestivos en vacas.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Relación entre los niveles plasmáticos de selenio y las diferentes enfermedades prostáticas

Several studies have demonstrated an inverse relation between serum selenium levels (Se) and advanced prostate cancer (PCa). Objective: To determine and compare selenium plasma levels in patients with different prostatic pathologies. Material and methods: It is a transversal, descriptive and comparative study. A sample of 64 men between 50 and 80 years old were selected for the study between 2007 and 2009. All volunteers underwent a digital rectal examination, prostate specific antigen level, ultrasound and transrectal prostate biopsy (1214 chips). Prostate cancer was subclassified according to Gleason Score. Selenium was determined indirectly by serum Glutathione peroxidase (Kit Ransel, Randox SRL, Crumlin, UK). Statistical analysis was performed using ANOVA I (p<0.05). Results: Glutathione Peroxidase level was 33.75±2.36 mg/ml in control patients. A decrease of 31.6% was observed in patients with BPH (23.08±1.57 mg/ml) and of (63.6%) in subjects with prostate cancer (12.28±1.03 mg/ml) (p<0,0001). There was no correlation with the Gleason Score. Conclusion: Serum Seleniun is lower in patients with prostatic pathologies being even more important in cancer patients regardless the Gleason Score.Fil: López Fontana, Constanza Matilde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad "Juan Agustín Maza". Facultad de Farmacia y Bioquímica; ArgentinaFil: Pérez Elizalde, R. F.. Universidad "Juan Agustín Maza". Facultad de Farmacia y Bioquímica; ArgentinaFil: Vanrell, M. C. M.. Universidad "Juan Agustín Maza". Facultad de Farmacia y Bioquímica; ArgentinaFil: Recalde, Gabriela María. Universidad "Juan Agustín Maza". Facultad de Farmacia y Bioquímica; ArgentinaFil: Uvilla, A. L.. Universidad "Juan Agustín Maza". Facultad de Farmacia y Bioquímica; ArgentinaFil: López Laur, J. D.. Universidad "Juan Agustín Maza". Facultad de Farmacia y Bioquímica; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentin

Local delivery of optimized nanobodies targeting the PD-1/PD-L1 axis with a self-amplifying RNA viral vector induces potent antitumor responses

Despite the success of immune checkpoint blockade for cancer therapy, many patients do not respond adequately. We aimed to improve this therapy by optimizing both the antibodies and their delivery route, using small monodomain antibodies (nanobodies) delivered locally with a self-amplifying RNA (saRNA) vector based on Semliki Forest virus (SFV). We generated nanobodies against PD-1 and PD-L1 able to inhibit both human and mouse interactions. Incorporation of a dimerization domain reduced PD-1/PD-L1 IC50 by 8- and 40-fold for antiPD-L1 and anti-PD-1 nanobodies, respectively. SFV viral particles expressing dimeric nanobodies showed a potent antitumor response in the MC38 model, resulting in >50% complete regressions, and showed better therapeutic efficacy compared to vectors expressing conventional antibodies. These effects were also observed in the B16 melanoma model. Although a short-term expression of nanobodies was observed due to the cytopathic nature of the saRNA vector, it was enough to generate a strong proinflammatory response in tumors, increasing infiltration of NK and CD8+ T cells. Delivery of the SFV vector expressing dimeric nanobodies by local plasmid electroporation, which could be more easily translated to the clinic, also showed a potent antitumor effect