Kinetic energy distributions of atomic ions from disintegration of argon containing nanoclusters in moderately intense nanosecond laser fields: Coulomb explosion or hydrodynamic expansion.

We report kinetic energies (KE) of multiply charged atomic ions (MCAI) from interactions of moderately intense nanosecond lasers at 532 nm with argon containing clusters, including neat and doped clusters with a trace amount of trichlorobenzene. We develop a mathematical method to retrieve speed and thereby kinetic energy information from analyzing the time-of-flight profiles of the MCAI. This method should be generally applicable in detections of energetic charged particles with high velocities, a realm where velocity map imaging is inadequate. From this analysis, we discover that the KE of MCAI from doped clusters demonstrates a quadratic dependence on the charge of the atomic ions, while for neat clusters, the dependence is cubic. This result confirms the nature of the cluster disintegration process to be dominated by Coulomb explosion. This result bears more similarity to reports from extreme vacuum ultraviolet (EUV) fields with similar intensities, than to reports from near infrared (NIR) intense laser fields. However, the charge state distribution from our experiment is the opposite: we observe more higher charge state ions than reported in EUV fields, and our charge state distribution is actually similar to those reported in NIR fields. We also report a significant effect of the external electric field on the charge state distribution of the atomic ions: the presence of an electric field can significantly increase the charge from the atomic ions, as shown by a three-fold reduction in the average kinetic energy per charge. Although molecular dynamics simulations have been implemented for experiments in the EUV and NIR, our results allude to the need of a concerted effort in this regime of moderately intense nanosecond laser fields. The significant decrease in charge state distribution and the significant increase in KE from doped clusters, compared with neat clusters, is a telltale sign that the true interaction time between the laser field and the cluster may be substantially shorter than the duration of the laser, a welcome relief for molecular dynamics simulations.

Toxicidad a dosis repetida e inmunogenicidad en Cercopithecus aethiops, del candidato vacunal SOBERANA 01 (FINLAY-FR-01) contra el coronavirus de tipo 2 causante del síndrome respiratorio agudo severo / Repeated dose toxicity and immunogenicity in Cercopithecus aethiops of SARS-CoV-2 SOBERANA 01 (FINLAY-FR-01) vaccine candidate

En el Instituto Finlay de Vacunas se desarrolló el candidato vacunal SOBERANA 01 (FINLAY-FR-01) contra el coronavirus de tipo 2 causante del síndrome respiratorio agudo severo. Este trabajo tuvo como objetivo evaluar la inmunogenicidad y posibles efectos toxicológicos del candidato vacunal SOBERANA 01 (FINLAY-FR-01 en Cercopithecus aethiops. Se utilizaron cinco primates no humanos (hembras), de 1-3 años de edad y 1-4 kg de peso corporal, distribuidos en dos grupos experimentales: Control (Solución Salina Fisiológica) y Tratado SOBERANA 01 (FINLAY-FR-01). El estudio se extendió por 84 días, en un esquema a dosis repetida de cuatro inmunizaciones los días 0, 28, 56 y 70. Se realizaron observaciones clínicas diarias, peso corporal, signos vitales (temperatura rectal, frecuencia respiratoria, y frecuencia cardíaca), exámenes electrocardiográficos, toma de la temperatura del sitio de inyección, musculometría e irritabilidad dérmica. Fueron realizados exámenes de hematología, bioquímica sanguínea, así como estudios inmunológicos. El ensayo concluyó con una supervivencia del 100por ciento, no se manifestaron signos de toxicidad, no hubo variaciones hematológicas, ni de la bioquímica sanguínea asociadas a la sustancia de ensayo. Además, no se observaron efectos locales en el sitio de administración. Por último, el candidato vacunal resultó inmunogénico, ya que se indujeron títulos altos de IgG anti-RBD, así como de la inhibición de la unión de RBD a ACE2(AU)

At Finlay Vaccine Institute has been developed the vaccine candidate SOBERANA 01 (FINLAY-FR-01) against SARS-CoV-2 virus, causing COVID-19. This work aims to evaluate the immunogenicity and possible toxicological effects of the SOBERANA 01 (FINLAY-FR-01) vaccine candidate in Cercopithecus aethiops. Five non-human primates (females) from 1-3 years old and 1-4 kg of body weight were distributed in two experimental groups: Control (Physiological Saline Solution) and Treated (SOBERANA 01 FINLAY-FR-01). The study extended through 84 days, in a repeated dose schedule of four immunizations on days 0, 28, 56, and 70. Daily clinical observations, body weight, vital signs (rectal temperature, respiratory rate, and heart rate), electrocardiographic examinations, temperature of the injection site, musculometry and dermic irritability, were performed. Hematological and blood biochemistry tests, as well as immunological studies were assessed. At the end of the assay 100percent survival was obtained, there were no signs of toxicity neither hematological or blood biochemistry variations associated with the test substance. In addition, no local effects were observed at the administration site. Finally, the vaccine candidate was immunogenic, since high titers of anti-RBD IgG, as well as inhibition of the RBD to ACE2 binding were induced(AU)

An Integrated Approach for the Early Detection of Endometrial and Ovarian Cancers (Screenwide Study): Rationale, Study Design and Pilot Study.

Screenwide is a case-control study (2017−2021) including women with incident endometrial and ovarian cancers (EC and OC), BRCA1/2 and MMR pathogenic variant carriers, and age-matched controls from three centers in Spain. Participants completed a personal interview on their sociodemographic factors, occupational exposure, medication, lifestyle, and medical history. We collected biological specimens, including blood samples, self-collected vaginal specimens, cervical pap-brush samples, uterine specimens, and, when available, tumor samples. The planned analyses included evaluation of the potential risk factors for EC/OC; evaluation of molecular biomarkers in minimally invasive samples; evaluation of the cost-effectiveness of molecular tests; and the generation of predictive scores to integrate different epidemiologic, clinical, and molecular factors. Overall, 182 EC, 69 OC, 98 BRCA pathogenic variant carriers, 104 MMR pathogenic variant carriers, and 385 controls were enrolled. The overall participation rate was 85.7%. The pilot study using 61 samples from nine EC cases and four controls showed that genetic variants at the variant allele fraction > 5% found in tumors (n = 61 variants across the nine tumors) were detected in paired endometrial aspirates, clinician-collected cervical samples, and vaginal self-samples with detection rates of 90% (55/61), 79% (48/61), and 72% (44/61) by duplex sequencing, respectively. Among the controls, only one somatic mutation was detected in a cervical sample. We enrolled more than 800 women to evaluate new early detection strategies. The preliminary data suggest that our methodological approach could be useful for the early detection of gynecological cancers.

Immuno-toxicological evaluation of her1 cancer vaccine in non-human primates: a 6-month subcutaneous study.

Purpose: A vaccine composition based on the extracellular domain of the human epidermal growth factor receptor 1 (HER1-ECD) and the combination of VSSP (very small size proteoliposomes) and Montanide ISA 51 adjuvants when used by intramuscular route, demonstrated promising results in preclinical studies. However, in order to avoid potential adverse events due to the use of Montanide, it is proposed to modify the vaccine formulation by using VSSP (very small size proteoliposomes) adjuvant alone, and to evaluate the quality of subcutaneously induced immune response. This study aimed to assess the immunotoxicological effects of HER1 vaccine in Cercopithecus aethiops.Materials and methods: Fifteen monkeys were randomized into four groups: Negative Control (Tris/NaCl, s.c.), Positive Control (200 µg HER1-ECD/VSSP/Montanide ISA-51 VG, i.m), Low Dose (200 µg HER1-ECD/VSSP/Tris NaCl, s.c.) and High Dose (800 µg HER1-ECD/VSSP/Tris NaCl, s.c). All monkeys received 7 doses and were daily inspected for clinical signs. Body weight, rectal temperature, cardiac and respiratory rates were measured during the study, and electrocardiographical and ophthalmological studies were performed. Humoral and cellular immune response and clinical pathology parameters were analyzed.Results: Animal's survival in the study was 100% (n = 15). Administration site reactions were observed in the Positive Control animals (n = 4). HER1 vaccine administered subcutaneously (High Dose Group) achieved good IgG antibody titers although lower than the Positive Control group, but with higher ability to inhibit HER1 phosphorylation. Conclusions: This suggests that the alternative of eliminating the use of Montanide in the HER1 vaccine preparation and the using subcutaneous route is feasible.

Anti-inflammatory activity of Jefea gnaphalioides (a. gray), Astereaceae.

BACKGROUND: Inflammation is a symptom associated with many diseases. This symptom is treated with steroidal and non-steroidal anti-inflammatory drugs, which can cause severe side effects when used as long-term treatments. Natural products are an alternative source of new compounds with anti-inflammatory activity. Jefea gnaphalioides (Astereaceae) (A. Gray) is a plant species used to treat inflammatory problems, in Mexico. This study determined the anti-inflammatory activity and the composition of the methanol extract of Jefea gnaphalioides (MEJG). METHODS: The extract was obtained by heating the plant in methanol at boiling point for 4 h, and then the solvent was evaporated under vacuum (MEJG). The derivatization of the extract was performed using Bis-(trimethylsilyl) trifluoroacetamide, and the composition was determined by GC-MS. Total Phenols and flavonoids were determined by Folin-Ciocalteu AlCl3 reaction respectively. The antioxidant activity of MEJG was determined by DPPH method. The acute and chronic anti-inflammatory effects were evaluated on a mouse ear edema induced with 12-O-Tetradecanoylphorbol-13-acetate (TPA). Acute oral toxicity was tested in mice at doses of MEJG of 5000, 2500 and 1250 mg/kg. The levels of NO, TNF-α, IL-1ß and IL-6 were determinate in J774A.1 macrophages stimulated by Lipopolysaccharide. The production of inflammatory interleukins was measured using commercial kits, and nitric oxide was measured by the Griess reaction. RESULTS: The anti-inflammatory activity of MEJG in acute TPA-induced ear edema was 80.7 ± 2.8%. This result was similar to the value obtained with indomethacin (IND) at the same dose (74.3 ± 2.8%). In chronic TPA-induced edema at doses of 200 mg/kg, the inhibition was 45.7%, which was similar to that obtained with IND (47.4%). MEJG have not toxic effects even at a dose of 5000 mg/kg. MEJG at 25, 50, 100 and 200 µg/mL decreased NO, TNF-α, IL-1ß and IL-6 production in macrophages stimulated with LPS. The major compounds in MEJG were α-D-Glucopyranose (6.71%), Palmitic acid (5.59%), D-(+)-Trehalose (11.91%), Quininic acid (4.29%) and Aucubin (1.17%). Total phenolic content was 57.01 mg GAE/g and total flavonoid content was 35.26 mg QE/g MEJG had antioxidant activity. CONCLUSIONS: MEJG has anti-inflammatory activity.

Campo magnético de frecuencia extremadamente baja: Seguridad de su aplicación a nivel del sistema nervioso central / Magnetic field of extremely low frequency: Safety of its application at the level of the central nervous system

Introducción: La enfermedad cerebrovascular constituye un importante problema de salud a nivel mundial. En la actualidad se desarrollan investigaciones científicas dedicadas al estudio de los efectos del campo magnético de frecuencia extremadamente baja para su tratamiento. No es suficientemente clara la información acerca de su inocuidad en las dosis estudiadas. Objetivo: Estudiar la seguridad de la aplicación del campo magnético de frecuencia extremadamente baja a nivel del sistema nervioso central a través de un estudio toxicológico a dosis aguda, repetida y ensayo de micronúcleos en médula ósea. Métodos: Se conformaron tres grupos experimentales con ratas Sprague Dawley Cenp:SPRD jóvenes y sanas para los experimentos de toxicidad y ratones CENP: NMRI para la evaluación mutagénica. Se utilizaron controles negativos no tratados. En el ensayo de micronúcleos se incorporó un grupo control positivo al que se administró Ciclofosfamida por vía intraperitoneal. Se aplicó un campo magnético no homogéneo con niveles de inducción magnética de 6,5 y 15 mT, tomando como referencia el valor máximo sobre la superficie de la bobina. Para la aplicación del campo magnético la bobina estimuladora se colocó sobre la cabeza asegurando la exposición completa del encéfalo. Resultados: En ninguno de los ensayos se detectaron signos de toxicidad. Se comprobó así mismo que no se indujeron efectos genotóxicos ni citotóxicos sobre las células somáticas. Conclusiones: El tratamiento con campo magnético de frecuencia extremadamente baja a nivel del sistema nervioso central en las condiciones experimentales y dosis estudiadas es seguro(AU)

Introduction: Stroke is a major health problem all over the world. Nowadays are developed scientific researches devoted to the study of extremely low frequency magnetic field effects over this illness. The information about it safety is unclear yet. Objective: To study the safety of extremely low frequency magnetic field applied at central nervous system level wasby means ofa toxicological assay (Acute, repeated doses and micronucleus in bone marrow assay) Methods: Three experimental groups were made with Sprague Dawley Cenp: SPRD young and healthy rats for toxicity experiments and CENP: NMRI mice for mutagen evaluation. Untreated negative controls were used. In the micronucleus assay, an additional positive control group was included. This group received Cyclophosphamide by intraperitoneal administration. Was applied a non-homogenousmagnetic fieldof 6,5 and 15 mT, taken as reference the maximum value over the coil surface. The coil was positioned over the head, ensuring full exposure of brain to magnetic field. Results : In none of trials were detected any sign of toxicity. It was also found no genotoxic or cytotoxic effects induced on somatic cells. Conclusions : These results indicated the safety of treatmentwith extremely low frequency magnetic field at central nervous system level for experimental conditions and doses studied(AU)

Zirconium Phosphate Nanoplatelet Potential for Anticancer Drug Delivery Applications.

Zirconium phosphate (ZrP) nanoplatelets can intercalate anticancer agents via an ion exchange reaction creating an inorganic delivery system with potential for cancer treatment. ZrP delivery of anticancer agents inside tumor cells was explored in vitro. Internalization and cytotoxicity of ZrP nanoplatelets were studied in MCF-7 and MCF-10A cells. DOX-loaded ZrP nanoplatelets (DOX@ZrP) uptake was assessed by confocal (CLSM) and transmission electron microscopy (TEM). Cytotoxicity to MCF-7 and MCF-10A cells was determined by the MTT assay. Reactive Oxy- gen Species (ROS) production was analyzed by fluorometric assay, and cell cycle alterations and induction of apoptosis were analyzed by flow cytometry. ZrP nanoplatelets were localized in the endosomes of MCF-7 cells. DOX and ZrP nanoplatelets were co-internalized into MCF-7 cells as detected by CLSM. While ZrP showed limited toxicity to MCF-7 cells, DOX@ZrP was cytotoxic at an IC50 similar to that of free DOX. Meanwhile, DOX lC50 was significantly lower than the equivalent concentration of DOX@ZrP in MCF-10A cells. ZrP did not induce apoptosis in both cell lines. DOX and DOX@ZrP induced significant oxidative stress in both cell models. Results suggest that ZrP nanoplatelets are promising as carriers of anticancer agents into cancer cells.

Non-clinical immuno-toxicological evaluation of HER1 cancer vaccine in non-human primates: a 12-month study.

Human epidermal growth factor receptor (HER1) constitutes a tumor associated antigen. Its overexpression in many epithelial tumors has been associated with bad prognosis and poor survival. Cancer vaccine based on the extracellular domain (ECD) of HER1 and adjuvated in very small sized proteoliposomes (VSSP) and Montanide ISA 51-VG is a new and complementary approach for the treatment of epithelial tumors. The present study deals with the immunogenicity of this vaccine in Macaca fascicularis monkeys and evaluation of its toxicity during 12 months. Twelve monkeys were randomized into two groups of 3 animals per sex: control and vaccinated. Treated monkeys received 9 doses of vaccination and were daily inspected for clinical signs. Body weight, rectal temperature, cardiac and respiratory rates were measured during the study. Humoral immune response, clinical pathology parameters and delayed type hypensensitivity were analyzed. Skin biopsy was performed at the end of the study in all animals. Animal's survival in the study was 100% (n=12). Local reactions were observed at the administration site of four treated animals (n=6), with two showing slight inflammatory cutaneous damage. Clinical pathology parameters were not affected. HER1 vaccine induced high IgG antibodies titers in the treated animals even when DTH was not observed. The induced antibodies recognized HER1+ tumor cell lines, decreased HER1 phosphorylation and showed anti-proliferative and pro-apoptotic effects in H125 cells. In general the present study showed that HER1 vaccine induced specific immune response in M. fascicularis monkeys and was well tolerated, suggesting it could be safely used in clinical studies in epithelial cancer patients.

Toxicidad crónica de polvo de taninos obtenidos de corteza de Pinus caribaea Morelet por vía oral en ratas / Chronic oral toxicity of tannin powders obtained from bark of Pinus caribaea Morelet in rats

INTRODUCCIÓN: se han demostrado los efectos antimutagénicos y no genotóxicos de los taninos de Pinus caribaea Morelet, así como su influencia en la mejoría de la calidad de vida de pacientes. OBJETIVOS: evaluar la toxicidad crónica del polvo de taninos obtenido de corteza de P. caribaea por vía oral. MÉTODOS: se realizó un estudio de toxicidad crónica (6 meses) por vía oral en ratas Cenp:SPRD. Se conformaron un grupo control y 3 tratados (1, 2,5 y 5 mg/kg/d/6 meses). Se realizaron observaciones clínicas diarias. El peso corporal y los consumos de agua y alimento se midieron semanalmente. Al inicio, en la semana 13 y al final del estudio se realizaron exámenes de laboratorio clínico. Al concluir los 6 meses se sacrificaron todos los animales y se efectuó necropsia completa de cada uno, así como el estudio microscópico de los órganos y tejidos de los animales de los grupos Dosis alta y control. RESULTADOS: durante el estudio murió 1 hembra del gurpo Dosis baja, el resto de los animales alcanzó el final del estudio con buen estado. Los signos clínicos descritos estuvieron distribuidos por todos los grupos y no guardaron relación con la sustancia de ensayo. La curva de peso corporal fue similar para todos los grupos. El consumo de agua se incrementó en los animales tratados con la dosis mayor, el consumo de alimento no se vio afectado. Los parámetros de laboratorio clínico presentaron diferencias, aunque se mantuvieron dentro de los rangos normales reportados para la especie. Los hallazgos de anatomía patológica no guardaron relación con la administración del polvo de taninos. CONCLUSIONES: la administración oral durante 6 meses del polvo de taninos de corteza de P. caribaea no produjo toxicidad.

INTRODUCTION: effects of antimutagenic and non-genotoxic agents of tannins from Pinus caribaea Morelet, as well as its influence in improvement of quality life of patients. OBJECTIVES: to assess chronic oral toxicity of tannin powder obtained from bark of P. caribaea. METHODS: we performed a study on chronic toxicity (6 months) per os in Cenp:SPRD rats. We made clinical observations daily. There was a control group and 3 treated (1, 2, 5 and 5 mg/kg/d/6 months). We performed clinical observations daily. Body weight and water and food consumptions were measured weekly. At the beginning, in 13 week and at the end of study, we carried out clinical laboratory examinations. At 6 months all animals were scarified and we made a complete necropsy of each, as well as a microscopical study of organs and tissues of animals in groups of higher dose and control. RESULTS: during study a female in lower dose group died, the remainder finished the study in a good sate. Clinical signs described were distributed by all groups and had not relation with assay substance. Body weight curve was similar for all groups. Water consumption increased in animals treated with the higher dose, but the food consumption was normal. Clinical laboratory parameters had differences, although they were within normal ranks reported for the species. Findings of pathologic anatomy have not relation to administration of tannin powders. CONCLUSIONS: There was not toxicity with per os administration during 6 months of tannin powders from bark of P. caribaea.

Toxicidad crónica de polvo de taninos obtenidos de corteza de Pinus caribaea Morelet por vía oral en ratas / Chronic oral toxicity of tannin powders obtained from bark of Pinus caribaea Morelet in rats

INTRODUCCIÓN: se han demostrado los efectos antimutagénicos y no genotóxicos de los taninos de Pinus caribaea Morelet, así como su influencia en la mejoría de la calidad de vida de pacientes. OBJETIVOS: evaluar la toxicidad crónica del polvo de taninos obtenido de corteza de P. caribaea por vía oral. MÉTODOS: se realizó un estudio de toxicidad crónica (6 meses) por vía oral en ratas Cenp:SPRD. Se conformaron un grupo control y 3 tratados (1, 2,5 y 5 mg/kg/d/6 meses). Se realizaron observaciones clínicas diarias. El peso corporal y los consumos de agua y alimento se midieron semanalmente. Al inicio, en la semana 13 y al final del estudio se realizaron exámenes de laboratorio clínico. Al concluir los 6 meses se sacrificaron todos los animales y se efectuó necropsia completa de cada uno, así como el estudio microscópico de los órganos y tejidos de los animales de los grupos Dosis alta y control. RESULTADOS: durante el estudio murió 1 hembra del gurpo Dosis baja, el resto de los animales alcanzó el final del estudio con buen estado. Los signos clínicos descritos estuvieron distribuidos por todos los grupos y no guardaron relación con la sustancia de ensayo. La curva de peso corporal fue similar para todos los grupos. El consumo de agua se incrementó en los animales tratados con la dosis mayor, el consumo de alimento no se vio afectado. Los parámetros de laboratorio clínico presentaron diferencias, aunque se mantuvieron dentro de los rangos normales reportados para la especie. Los hallazgos de anatomía patológica no guardaron relación con la administración del polvo de taninos. CONCLUSIONES: la administración oral durante 6 meses del polvo de taninos de corteza de P. caribaea no produjo toxicidad(AU)

INTRODUCTION: effects of antimutagenic and non-genotoxic agents of tannins from Pinus caribaea Morelet, as well as its influence in improvement of quality life of patients. OBJECTIVES: to assess chronic oral toxicity of tannin powder obtained from bark of P. caribaea. METHODS: we performed a study on chronic toxicity (6 months) per os in Cenp:SPRD rats. We made clinical observations daily. There was a control group and 3 treated (1, 2, 5 and 5 mg/kg/d/6 months). We performed clinical observations daily. Body weight and water and food consumptions were measured weekly. At the beginning, in 13 week and at the end of study, we carried out clinical laboratory examinations. At 6 months all animals were scarified and we made a complete necropsy of each, as well as a microscopical study of organs and tissues of animals in groups of higher dose and control. RESULTS: during study a female in lower dose group died, the remainder finished the study in a good sate. Clinical signs described were distributed by all groups and had not relation with assay substance. Body weight curve was similar for all groups. Water consumption increased in animals treated with the higher dose, but the food consumption was normal. Clinical laboratory parameters had differences, although they were within normal ranks reported for the species. Findings of pathologic anatomy have not relation to administration of tannin powders. CONCLUSIONS: There was not toxicity with per os administration during 6 months of tannin powders from bark of P. caribaea(AU)