Hemispheric sensitivity to thematic role information derived from active and passive verbs: An event related brain potentials study

Recent research examining differences in the way the left (LH) and right (RH) hemispheres of the brain process language have used the visual half-field (VHF) paradigm to examine whether each hemisphere can independently process information from sentences. The current study expanded upon such work by using event related brain potential (ERP) measures to examine how the comprehension of thematic role knowledge, a process essential to successful sentence comprehension (MacDonald, Pearlmutter, & Seidenbeerg, 1994), is undertaken in each hemisphere. During language comprehension, agents (entities that initiate action in an event) depicted by nouns (e.g., cop) have been shown to be associated with verbs presented in active voice (e.g., present participle—cop was arresting), whereas patients (entities that have action imposed upon them—e.g., crook for the event arrest) are associated with verbs presented in passive voice (e.g., crook was arrested—Ferretti, McRae, Elman, & Ramshaw, 2005). Thus, the currently study examined how the cerebral hemispheres conjointly (Experiment 1) and independently (Experiment 2) process thematic fit (whether the noun and verb are thematically related) in conjunction with morphosyntactic information indicating whether a verb is in active (arresting), or passive (arrested) voice in order to further understand each hemisphere’s sentence processing abilities. In Experiment 1, ERP responses to verbs (presented centrally) preceded by a common agent noun and presented in related-active (e.g., The teacher was lecturing the man), unrelated active (e.g., The shepherd was lecturing the man), related-passive (e.g., The teacher was lectured by the man) and unrelated passive (e.g., The shepherd was lectured by the man), sentences were analyzed in order to examine the effects of relatedness and voice on the processing of the critical verb. Experiment 1 results showed that brainwave amplitudes demonstrated greater semantic facilitation for related active than for unrelated active verbs. However, this effect did not occur as strongly for passive verbs, indicating that the congruency between the agent and verb form significantly affected processing. In Experiment 2, the exact same experimental design was employed with the procedural variation that the critical verbs were presented 2⁰ to either the left or right of visual fixation, so only one hemisphere initially receives the information. Results from this experiment showed that with LH presentation, as with central presentation, related active verbs were processed more easily than unrelated active verbs and the magnitude of this effect was larger than that for analogous differences found with passive verbs (although sensitivity to relatedness for passive verbs was slightly larger than in Experiment 1). However, in the RH, differences in relatedness were found only for passive items indicating that sensitivity to relatedness differences in this hemisphere may be mediated more by frequency differences between verb forms than with LH processing (or central presentation). These results provide evidence against the theoretical contentions that the RH is only sensitive to simple word-level semantic relations (e.g., Faust, 1998), and are supportive of an ‘expectancy’ account of LH language processing (e.g., Coulson et al., 2005; Federmeier & Kutas, 1999)

La importancia científica de las primeras colecciones de fósiles antárticos recolectados por la expedición antártica sueca de 1901-1903

En el año 1901, el geólogo sueco Otto Nordenskjöld junto a otros exploradores realizaron un viaje a la Antártida, quedando accidentalmente varados durante 2 años. A fines de 1903 fueron rescatados por la Corbeta Uruguay de la Armada Argentina, al mando del Capitán Irízar. Durante su forzosa estadía en el continente antártico, estos exploradores recolectaron los primeros fósiles. Al momento del rescate muchos de los fósiles fueron llevados a Europa y hoy en día son exhibidos en importantes museos, mientras otros quedaron en la casa de la isla Cerro Nevado (al este de la Península Antártica), una cabaña prefabricada de madera donde permanecieron los exploradores durante su estadía. En las sucesivas campañas antárticas, estos fósiles fueron llevados al Instituto Antártico Argentino (IAA) formando parte de una colección histórica. Con el relevamiento del Edificio Histórico del IAA estos fósiles fueron rescatados, catalogados y resguardados fin de recuperar su valor científico y cultural. El presente trabajo tiene dos objetivos: por un lado, presentar los fósiles hallados en la casa de Cerro Nevado, analizando el impacto que provocaron los hallazgos paleontológicos para la comunidad científica a comienzos de 1900. En segundo lugar, se discuten las motivaciones personales que llevaron a Nordenskjöld a realizar el viaje a la Antártida y se describe el contexto científico-histórico de la época, destacando las teorías geológicas vigentes. También se discute el rol de los Congresos Internacionales de Geografía de Londres y Berlín desarrollados a fines del siglo XIX, en la promoción de la investigación científica en la Antártida.Fil: Rodriguez Amenabar, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Geología. Cátedra de Paleontología; Argentina. Ministerio de Relaciones Exteriores, Comercio Interno y Culto. Dirección Nacional del Antártico. Instituto Antártico Argentino; ArgentinaFil: Schwint, Clara. No especifíca;Reunión de Comunicaciones de la Asociación Paleontológica ArgentinaPuerto MadrynArgentinaAsociación Paleontológica Argentin

The radiobiological principles of boron neutron capture therapy: A critical review

The radiobiology of the dose components in a BNCT exposure is examined. The effect of exposure time in determining the biological effectiveness of γ-rays, due to the repair of sublethal damage, has been largely overlooked in the application of BNCT. Recoil protons from fast neutrons vary in their relative biological effectiveness (RBE) as a function of energy and tissue endpoint. Thus the energy spectrum of a beam will influence the RBE of this dose component. Protons from the neutron capture reaction in nitrogen have not been studied but in practice protons from nitrogen capture have been combined with the recoil proton contribution into a total proton dose. The relative biological effectiveness of the products of the neutron capture reaction in boron is derived from two factors, the RBE of the short range particles and the bio-distribution of boron, referred to collectively as the compound biological effectiveness factor. Caution is needed in the application of these factors for different normal tissues and tumors.Fil: Hopewell, J. W.. University of Oxford; Reino UnidoFil: Morris, G. M.. Brookhaven National Laboratory; Estados UnidosFil: Schwint, Amanda Elena. Comision Nacional de Energia Atomica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Coderre, J. A.. No especifíca

Angiogenesis in potentially malignant lesions and carcinomas during experimental oral carcinogenesis: a preliminary study in the hamster cheek pouch

AIM: To evaluate vascular morphology and density, angiogenic switch activation, vascular endothelial growth factor (VEGF) expression, and endothelial cell (EC) proliferation in the hamster cheek pouch (HCP) model of oral cancer. MATERIALS AND METHODS: Immunohistochemical detection of factor VIII, 5'-Bromo-2'-Deoxyuridine (BrdU) and VEGF was performed in pre-malignant and tumoral tissues. RESULTS: Activation of angiogenesis was detected adjacent to epithelial dysplasia. Vascularized area and perimeter (p<0.001) increased in dysplasias and tumors. Tumor blood vessels exhibited an enhanced vascular compression (p<0.001) and structural alterations. EC proliferation was similar in dysplasias and carcinomas. An increase in vascular density, EC proliferation and VEGF expression was found in potentially malignant tissues but not in carcinomas. CONCLUSION: The angiogenic switch occurs in the dysplastic stage preceding tumor development in the HCP model of oral cancer. In potentially malignant tissues, increased VEGF expression favors EC proliferation and an increase in vascular density. Conversely, in tumors, VEGF is no longer of pivotal importance.Fil: Aromando, Romina F.. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Raimondi, Ana Rosa. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pérez, Miguel A.. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Itoiz, Maria Elina. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Translational Radiobiological Boron Neutron Capture Therapy (BNCT) Studies for the Treatment of Different Pathologies: A Bench to Bedside Approach

Boron Neutron Capture Therapy (BNCT) is a binary cancer treatment modality that combines irradiation with a thermal or epithermal neutron beam with the administration of boron-10 carriers that are taken up preferentially by neoplastic cells. The high linear energy transfer alpha particles and recoiling 7 Li nuclei emitted during the boron-10 neutron-capture reaction 10B(n,α)7 Li, have a range of 5-9 µm in tissue and are known to have a high Relative Biological Effectiveness (RBE). In this way, BNCT would potentially target tumor tissue selectively, largely sparing normal tissue. Clinical trials of BNCT for the treatment of glioblastoma multiforme and/ or melanoma and, more recently, head and neck tumors, liver metastases, lung metastases and mesothelioma have been performed or are under way in Argentina, Europe, Japan, Taiwan, and the US. To date, the clinical results have shown a potential therapeutic advantage for this technique but undoubtedly leave room for improvement. Translational radiobiological studies in appropriate in vivo experimental models are pivotal to progress in this field. A significant part of our translational research efforts have been focused on exploring new applications of BNCT and optimizing BNCT for different pathologies, employing a bench to bedside approach that bridges the gap between research and clinical application. Although our work includes the assessment of the therapeutic potential of novel boron compounds in our experimental models, a large proportion of our studies have been devoted to optimize the delivery of boron compounds currently authorized for their use in humans such as Boron phenylalanine (BPA) and decahydrodecaborate (GB-10). In addition, we have designed and tested different BNCT treatment strategies tailored for different pathologies, for varying degrees of disease progression and for different clinical conditions of the patient. Some examples involve: 1) The combined use of BPA and GB-10 to improve tumor boron targeting homogeneity in the hamster cheek pouch oral cancer model, in a colon carcinoma liver metastases model in BDIX rats and in a diffuse lung metastases model in BDIX rats; 2) Aberrant tumor blood vessel normalization to improve boron delivery in the oral cancer model; 3) Sequential BNCT (BPA-BNCT followed by GB-10- BNCT with a 24-48 h interval) in the oral cancer model to optimize therapeutic efficacy and minimize mucositis in the dose-limiting precancerous tissue in the case of patients requiring abbreviated treatment; 4) Electroporation to improve the micro distribution of boron delivered by GB-10 in the oral cancer model; 5) Double applications of BNCT with 4-6 weeks interval to optimize therapeutic efficacy, reduce toxicity in terms of mucositis and inhibit the development of second primary tumors from precancerous tissue in the oral cancer model for the case of patients that do not require abbreviated treatment; 5) Assessment of the therapeutic efficacy and potential toxicity of BNCT in the liver metastases and diffuse lung metastases models in BDIX rats; 6) Local administration of GB10 or BPA for effective low dose Boron Neutron Capture Synovectomy (BNCS) for the treatment of Rheumatoid Arthritis in a model of antigen-induced arthritis in rabbits; 7) BNCT-induced local and abscopal effect in an ectopic model of colon carcinoma in BDIX rats. The knowledge gained from these radiobiological studies would contribute to design safe and effective clinical BNCT protocols. In particular, the BNCT protocols used to perform our ongoing and to date successful clinical-veterinary BNCT studies at RA-6 for cats and dogs with spontaneous head and neck cancer with no therapeutic option, are partially based on the lessons learnt from these translational studies.Fil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Gerencia de Area de Aplicaciones de la Tecnología Nuclear. Gerencia de Radiobiología (Centro Atómico Constituyentes); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Evaluation of mass spectrometric methods for detection of the anti-protozoal drug imidocarb

Imidocarb [N,N\u27-bis[3-(4,5-dihydro-1H-imidazol-2-yl)phenyl]urea, C19H20N6O1, m.w. 348.41] is a symmetrical carbanilide derivative used to treat disease caused by protozoans of the Babesia genus. Imidocarb, however, is also considered capable of suppressing Babesia-specific immune responses, allowing Babesia-positive horses to pass a complement fixation test (CFT) without eliminating the infection. This scenario could enable Babesia-infected horses to pass CFT-based importation tests. It is imperative to unequivocally identify and quantify equine tissue residues of imidocarb by mass spectrometry to address this issue. As a pretext to development of sensitive tissue assays, we have investigated possibilities of mass spectrometric (MS) detection of imidocarb. Our analyses disclosed that an unequivocal mass spectral analysis of imidocarb is challenging because of its rapid fragmentation under standard gas chromatography (GC)-MS conditions. In contrast, solution chemistry of imidocarb is more stable but involves distribution into mono- and dicationic species, m/z 349 and 175, respectively, in acid owing to the compound\u27s inherent symmetrical nature. Dicationic imidocarb was the preferred complex as viewed by either direct infusion-electrospray-MS or by liquid chromatography (LC)-MS. Dicationic imidocarb multiple reaction monitoring (MRM: m/z 175 → 162, 145, and 188) therefore offer the greatest opportunities for sensitive detection and LC-MS is more likely than GC-MS to yield a useful quantitative forensic analytical method for detecting imidocarb in horses

Teachings of our translational studies on boron neutron capture therapy (BNCT): thinking “outside the box”

BNCT is a technique for the treatment of solid tumors. BNCT is considered a binary technique because it involves two components that exert little or no action individually but induce a significant effect when they combine. BNCT is based on the combination of neutron irradiation and the administration of 10B compounds that are incorporated selectively by tumor tissue via different mechanisms, depending on the boron carrier.Fil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Palmieri, Mónica Alejandra. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Optimization of the classical oral cancerization protocol in hamster to study oral cancer therapy

Objective(s): The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. “Short” pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. Materials and methods: We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. Results: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. Conclusion(s): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.Objective(s): The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. “Short” pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. Materials and methods: We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. Results: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. Conclusion(s): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.Fil: Santa Cruz, Iara Sofía. Comisión Nacional de Energía Atómica; ArgentinaFil: Santa Cruz, Iara Sofía. Comisión Nacional de Energía Atómica; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Trivillin, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Itoiz, María Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Itoiz, María Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Guidobono, Juan Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Guidobono, Juan Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Schwint, Amanda Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Schwint, Amanda Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Monti Hughes, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Monti Hughes, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentin

Boron Neutron Capture Therapy (BNCT) in an oral precancer model: Therapeutic benefits and potential toxicity of a double application of BNCT with a six-week interval

Given the clinical relevance of locoregional recurrences in head and neck cancer, we developed a novel experimental model of premalignant tissue in the hamster cheek pouch for long-term studies and demonstrated the partial inhibitory effect of a single application of Boron Neutron Capture Therapy (BNCT) on tumor development from premalignant tissue. The aim of the present study was to evaluate the effect of a double application of BNCT with a 6 week interval in terms of inhibitory effect on tumor development, toxicity and DNA synthesis. We performed a double application, 6 weeks apart, of (1) BNCT mediated by boronophenylalanine (BPA-BNCT); (2) BNCT mediated by the combined application of decahydrodecaborate (GB-10) and BPA [(GB-10 + BPA)-BNCT] or (3) beam-only, at RA-3 nuclear reactor and followed the animals for 8 months. The control group was cancerized and sham-irradiated. BPA-BNCT, (GB-10 + BPA)-BNCT and beam-only induced a reduction in tumor development from premalignant tissue that persisted until 8, 3, and 2 months respectively. An early maximum inhibition of 100% was observed for all 3 protocols. No normal tissue radiotoxicity was detected. Reversible mucositis was observed in premalignant tissue, peaking at 1 week and resolving by the third week after each irradiation. Mucositis after the second application was not exacerbated by the first application. DNA synthesis was significantly reduced in premalignant tissue 8 months post-BNCT. A double application of BPA-BNCT and (GB-10 + BPA)-BNCT, 6 weeks apart, could be used therapeutically at no additional cost in terms of radiotoxicity in normal and dose-limiting tissues.Fil: Monti Hughes, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Comision Nacional de Energia Atomica. Gerencia D/area de Energia Nuclear. Gerencia de Ingenieria Nuclear (cab). Departamento de Reactores de Investigacion.; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Thorp, Silvia Inés. Comision Nacional de Energia Atomica. Gerencia de Area Carem. Departamento de Instrumentacion y Cableado (cab).; ArgentinaFil: Miller, Marcelo. Comision Nacional de Energia Atomica. Gerencia de Area Carem. Departamento de Instrumentacion y Cableado (cab).; ArgentinaFil: Itoiz, María Elina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Aromando, Romina F.. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Molinari, Ana Julia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Trivillin, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Schwint, Amanda Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentin

Tumor blood vessel ''normalization'' improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer

We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer. Blood vessel normalization was induced by two doses of thalidomide in tumor-bearing hamsters on 2 consecutive days. All studies in thalidomide-treated animals were performed 48 h after the first dose of thalidomide, previously established as the window of normalization. Biodistribution studies were performed with BPA at a dose of 15.5 mg 10B/kg in thalidomide-treated (Th+) and untreated (Th–) tumorbearing hamsters. The effect of blood vessel normalization prior to BPA administration on the efficacy of BNCT was assessed in in vivo BNCT studies at the RA-3 Nuclear Reactor in tumor-bearing hamsters. Group I was treated with BPABNCT after treatment with thalidomide (Th+ BPA-BNCT). Group II was treated with BPA-BNCT alone (Th– BPABNCT). Group III was treated with the beam only after treatment with thalidomide (Th+ BO), and Group IV was treated with the beam only (Th– BO). Groups I and II were given the same dose of BPA (15.5 mg 10B/kg), and all groups (I–IV) were exposed to the same neutron fluence. Two additional groups were treated with the beam only at a higher dose to exacerbate mucositis in precancerous tissue and to explore the potential direct protective effect of thalidomide on radiation-induced mucositis in a scenario of more severe toxicity, i.e. Group V (Th+ hdBO) and Group VI (Th– hdBO). The animals were followed for 28 days. Biodistribution studies revealed no statistically significant differences in gross boron content between Th+ and Th– animals. Overall tumor control (complete response + partial response) at 28 days post-treatment was significantly higher for Group I (Th+ BPA-BNCT) than for Group II (Th– BPA-BNCT): 84 6 3% compared to 67 6 5%. Pretreatment with thalidomide did not induce statistically significant changes in overall tumor control induced by the beam only, i.e. 15 6 5% in Group III (Th+ BO) and 18 6 5% in Group IV (Th– BO), or in overall tumor control induced by the high-dose beam only, i.e. 60 6 7% in Group V (Th+ hdBO) and 47 6 10% in Group VI (Th– hdBO). BPA-BNCT alone (Group II) induced mucositis in precancerous tissue that reached Grades 3–4 in 80% of the animals, whereas pretreatment with thalidomide (Group I) prevented mucositis Grades 3 and 4 completely. Beam-only Group III (Th+ BO) exhibited only Grade 1 mucositis in precancerous tissue, whereas 17% of the animals in beamonly Group IV (Th– BO) reached Grade 2 mucositis. Highdose beam-only group V (Th+ hdBO) exhibited only Grade 2 mucositis, whereas high-dose beam-only group VI (Th– hdBO) reached Grade 3 mucositis in 83% of the animals. In all cases mucositis in precancerous tissue was reversible. No normal tissue radiotoxicity was observed with any of the protocols. Pretreatment with thalidomide enhanced the therapeutic efficacy of BNCT and reduced precancerous tissue toxicity.Fil: Molinari, Ana Julia. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Comisión Nacional de Energía Atómica. Centro Atómico Ezeiza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Monti Hughes, Andrea. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Heber, Elisa Mercedes. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Garabalino, Marcela Alejandra. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica. Centro Atómico Ezeiza; ArgentinaFil: Miller, Marcelo Eduardo. Comisión Nacional de Energía Atómica. Centro Atómico Ezeiza; ArgentinaFil: Itoiz, María Elina. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Universidad de Buenos Aires. Facultad de Odontología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aromando, Romina Flavia. Universidad de Buenos Aires. Facultad de Odontología; ArgentinaFil: Nigg, David W.. Idaho National Laboratory; Estados UnidosFil: Trivillin, Verónica Andrea. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schwint, Amanda Elena. Comisión Nacional de Energía Atómica. Gerencia de Área de Aplicaciones de la Tecnología Nuclear. Departamento de Radiobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin