Eficacia del rimadyl® en el control del dolor y la recuperación postquirúrgica después de una cirugía por dislocación abomasal

Se han estudiado los efectos de la aplicación de Rimadyl® (carprofeno 50 mg/ml) sobre la concentración de cortisol, temperatura rectal, frecuencia respiratoria, frecuencia cardiaca y motilidad ruminal, con el objetivo evaluar su eficacia en el control del dolor y la recuperación postquirúrgica, al aplicarlo antes de la cirugía por dislocación abomasal. Se seleccionaron 24 vacas de características similares que iban a someterse a cirugía por dislocación abomasal y se asignaron al azar a uno de los dos tratamientos experimentales: Rimadyl® o suero salino fisiológico. La aplicación de Rimadyl® disminuye (P=0,006) la concentración plasmática de cortisol (11,3 ng/mL vs 22,13 ng/mL). Con el tiempo se reducen (P=0,024) los niveles de cortisol plasmático. Esta reducción es más acusada (P=0,0003) con Rimadyl® a las 6 horas de su aplicación. La producción de leche postcirugía fue mayor en los animales que recibieron Rimadyl® en comparación con los que se les aplicó suero salino fisiológic

Discovery of the Optical Transient of the Gamma Ray Burst 990308

The optical transient of the faint Gamma Ray Burst 990308 was detected by the QUEST camera on the Venezuelan 1-m Schmidt telescope starting 3.28 hours after the burst. Our photometry gives $V = 18.32 \pm 0.07$, $R = 18.14 \pm 0.06$, $B = 18.65 \pm 0.23$, and $R = 18.22 \pm 0.05$ for times ranging from 3.28 to 3.47 hours after the burst. The colors correspond to a spectral slope of close to $f_{\nu} \propto \nu^{1/3}$. Within the standard synchrotron fireball model, this requires that the external medium be less dense than $10^{4} cm^{-3}$, the electrons contain $> 20$ of the shock energy, and the magnetic field energy must be less than 24% of the energy in the electrons for normal interstellar or circumstellar densities. We also report upper limits of $V > 12.0$ at 132 s (with LOTIS), $V > 13.4$ from 132-1029s (with LOTIS), $V > 15.3$ at 28.2 min (with Super-LOTIS), and a 8.5 GHz flux of $< 114 \mu Jy$ at 110 days (with the Very Large Array). WIYN 3.5-m and Keck 10-m telescopes reveal this location to be empty of any host galaxy to $R > 25.7$ and $K > 23.3$. The lack of a host galaxy likely implies that it is either substantially subluminous or more distant than a red shift of $\sim 1.2$.Comment: ApJ Lett submitted, 5 pages, 2 figures, no space for 12 coauthor

Evaluation of different bowel preparations for small bowel capsule endoscopy: a prospective, randomized, controlled study

To obtain an adequate view of the whole small intestine during capsule endoscopy (CE) a clear liquid diet and overnight fasting is recommended. However, intestinal content can hamper vision in spite of these measures. Our aim was to evaluate tolerance and degree of intestinal cleanliness during CE following three types of bowel preparation. PATIENTS AND METHODS: This was a prospective, multicenter, randomized, controlled study. Two-hundred ninety-one patients underwent one of the following preparations: 4 L of clear liquids (CL) (group A; 92 patients); 90 mL of aqueous sodium phosphate (group B; 89 patients); or 4 L of a polyethylene glycol electrolyte solution (group C; 92 patients). The degree of cleanliness of the small bowel was classified by blinded examiners according to four categories (excellent, good, fair or poor). The degree of patient satisfaction, gastric and small bowel transit times, and diagnostic yield were measured. RESULTS: The degree of cleanliness did not differ significantly between the groups (P = 0.496). Interobserver concordance was fair (k = 0.38). No significant differences were detected between the diagnostic yields of the CE (P = 0.601). Gastric transit time was 35.7 +/- 3.7 min (group A), 46.1 +/- 8.6 min (group B) and 34.6 +/- 5.0 min (group C) (P = 0.417). Small-intestinal transit time was 276.9 +/- 10.7 min (group A), 249.7 +/- 13.1 min (group B) and 245.6 +/- 11.6 min (group C) (P = 0.120). CL was the best tolerated preparation. Compliance with the bowel preparation regimen was lowest in group C (P = 0.008). CONCLUSIONS: A clear liquid diet and overnight fasting is sufficient to achieve an adequate level of cleanliness and is better tolerated by patients than other forms of preparation

Autoantibody screening in Guillain-Barré syndrome

Background: Guillain?Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. Methods: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. Results: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factor

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Apoptosis induction in Jurkat cells and sCD95 levels in women's sera are related with the risk of developing cervical cancer

<p>Abstract</p> <p>Background</p> <p>Currently, there is clear evidence that apoptosis plays an important role in the development and progression of tumors. One of the best characterized apoptosis triggering systems is the CD95/Fas/APO-1 pathway; previous reports have demonstrated high levels of soluble CD95 (sCD95) in serum of patients with some types of cancer. Cervical cancer is the second most common cancer among women worldwide. As a first step in an attempt to design a minimally invasive test to predict the risk of developing cervical cancer in patients with precancerous lesions, we used a simple assay based on the capacity of human serum to induce apoptosis in Jurkat cells. We evaluated the relationship between sCD95 levels and the ability to induce apoptosis in Jurkat cells in cervical cancer patients and controls.</p> <p>Methods</p> <p>Jurkat cells were exposed to serum from 63 women (20 healthy volunteers, 21 with cervical intraepithelial neoplasia grade I [CIN 1] and 22 with cervical-uterine carcinoma). The apoptotic rate was measured by flow cytometry using Annexin-V-Fluos and Propidium Iodide as markers. Serum levels of sCD95 and soluble CD95 ligand (sCD95L) were measured by ELISA kits.</p> <p>Results</p> <p>We found that serum from almost all healthy women induced apoptosis in Jurkat cells, while only fifty percent of the sera from women with CIN 1 induced cell death in Jurkat cells. Interestingly, only one serum sample from a patient with cervical-uterine cancer was able to induce apoptosis, the rest of the sera protected Jurkat cells from this killing. We were able to demonstrate that elimination of Jurkat cells was mediated by the CD95/Fas/Apo-1 apoptotic pathway. Furthermore, the serum levels of sCD95 measured by ELISA were significantly higher in women with cervical cancer.</p> <p>Conclusion</p> <p>Our results demonstrate that there is a strong correlation between low levels of sCD95 in serum of normal women and higher apoptosis induction in Jurkat cells. We suggest that an analysis of the apoptotic rate induced by serum in Jurkat cells and the levels of sCD95 in serum could be helpful during the prognosis and treatment of women detected with precancerous lesions or cervical cancer.</p

What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes

Incidence, clinical characteristics and management of inflammatory bowel disease in Spain: large-scale epidemiological study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD—Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)—during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100, 000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31–56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Measurement of the cosmic ray spectrum above 4×10^18 eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding 4×1018 eVis presented, which is based on the analysis of showers with zenith angles greater than60◦ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies.Above 5.3×1018 eV, the ?ankle?, the flux can be described by a power law E −γ with index γ = 2.70 ± 0.02 (stat) ± 0.1 (sys) followed by a smooth suppression region. For the energy(Es ) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find Es = (5.12 ± 0.25 (stat)−1.2 (sys))×10 eV.Fil: Aab, A.. Universität Siegen; AlemaniaFil: Abreu, P.. Universidade de Lisboa; PortugalFil: Aglietta, M.. Osservatorio Astrofisico di Torino; ItaliaFil: Ahn, E. J.. Fermilab; Estados UnidosFil: Al Samarai, I. Université Paris 11; FranciaFil: Allekotte, Ingomar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Almela, Daniel Alejandro. Universidad Tecnológica Nacional; ArgentinaFil: Asorey, Hernán Gonzalo. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Ave, M.. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Avila, G.. Observatorio Pierre Auger; ArgentinaFil: Bertou, Xavier Pierre Louis. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Contreras, F.. Observatorio Pierre Auger; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Dasso, Sergio Ricardo. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Dova, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Etchegoyen, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Figueira, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Freire, Martín Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Garcia, Beatriz Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Golup, Geraldina Tamara. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Gomez Berisso, Mariano. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Gómez Vitale, P. F.. Observatorio Pierre Auger; ArgentinaFil: González, N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Hampel, Matias Rolf. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Hansen, Patricia Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Harari, Diego Dario. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Jarne, Cecilia Gisele. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Josebachuili Ogando, Mariela Gisele. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Kleinfeller, J.. Observatorio Pierre Auger; ArgentinaFil: Lucero, A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Mariazzi, Analisa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Masías Meza, Jimmy Joel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Melo, Diego Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Micheletti, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Mollerach, Maria Silvia. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Pallotta, Juan Vicente. Ministerio de Defensa. Instituto de Investigaciones Científicas y Técnicas para la Defensa; ArgentinaFil: Piegaia, Ricardo Nestor. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Pieroni, Pablo Emanuel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Platino, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Purrello, Víctor Hugo. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Quel, E. J.. Ministerio de Defensa. Instituto de Investigaciones Científicas y Técnicas para la Defensa; ArgentinaFil: Ravignani, D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Ristori, Pablo Roberto. Ministerio de Defensa. Instituto de Investigaciones Científicas y Técnicas para la Defensa; ArgentinaFil: Rodriguez Rojo, J.. Observatorio Pierre Auger; ArgentinaFil: Roulet, Esteban. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Rovero, Adrian Carlos. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Sánchez, F.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Sato, R.. Observatorio Pierre Auger; ArgentinaFil: Scarso, C.. Observatorio Pierre Auger; ArgentinaFil: Sciutto, Sergio Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Sidelnik, Iván Pedro. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Squartini, R.. Observatorio Pierre Auger; ArgentinaFil: Suarez, F.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Supanitsky, Alberto Daniel. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Taborda Pulgarin, Oscar Alejandro. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Tapia, A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Videla, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; ArgentinaFil: Wahlberg, H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Wainberg, O.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Tecnología en Detección y Astroparticulas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astroparticulas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astroparticulas; Argentin

Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity

Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and T-cell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glyco-lipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined.We have constructed two structural analogues of HER-2 glyco-lipopeptide (HER-GLP) by synthesizing a chimeric peptide made of one universal CD4(+) epitope (PADRE) and one HER-2 CD8(+) T-cell epitope (HER(420-429)). The C-terminal end of the resulting CD4-CD8 chimeric peptide was coupled to a tumor carbohydrate B-cell epitope, based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules. The resulting HER glyco-peptide (HER-GP) was then linked to a palmitic acid moiety, attached either at the N-terminal end (linear HER-GLP-1) or in the middle between the CD4+ and CD8+ T cell epitopes (branched HER-GLP-2). We have investigated the uptake, processing and cross-presentation pathways of the two HER-GLP vaccine constructs, and assessed whether the position of linkage of the lipid moiety would affect the B- and T-cell immunogenicity and protective efficacy. Immunization of mice revealed that the linear HER-GLP-1 induced a stronger and longer lasting HER(420-429)-specific IFN-gamma producing CD8(+) T cell response, while the branched HER-GLP-2 induced a stronger tumor-specific IgG response. The linear HER-GLP-1 was taken up easily by dendritic cells (DCs), induced stronger DCs maturation and produced a potent TLR- 2-dependent T-cell activation. The linear and branched HER-GLP molecules appeared to follow two different cross-presentation pathways. While regression of established tumors was induced by both linear HER-GLP-1 and branched HER-GLP-2, the inhibition of tumor growth was significantly higher in HER-GLP-1 immunized mice (p<0.005).These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers