TPEN/TPGS (T2) combo dramatically reduces Philadelphia chromosome-positive pro-lymphoblastic B leukemia in BALB/c mice.

Acute lymphoblastic leukemia (ALL) is hematological neoplasia that affects human beings from early life to adulthood. Although ALL treatment has been effective, an important percentage of ALL patients are resilient to treatment. Therefore, there is an urgent need for testing a new combination of compounds for the treatment of this disease. Recently, combined TPEN and TPGS (T2 combo) have shown selective cytotoxic effects in vitro leukemia cells such as Jurkat, K562, and Ba/F3 cells. In this study, we aimed to test the effect of combined TPEN and TPGS agents (T2 combo) at a fixed dose (TPEN 5 mg/kg: TPGS 100 mg/kg) on leukemic Ba/F3-BCR-ABL P210 BALB-c mice model. We found that 4 successive 2-day apart intravenous injections of T2 combo showed a statistically significant reduction of Ba/F3 BCR-ABL leukemia cells (- 69%) in leukemia BALB/c mice (n = 6) compared to untreated leukemia group (n = 6). Moreover, the T2 combo was innocuous to non-leukemia BALB/c mice (n = 3) compared to untreated non-leukemia mice (control, n = 3). After treatments (day 42), all mice were left to rest until day 50. Outstandingly, the leukemia BALB/c mice treated with the T2 combo showed a lower percentage of Ba/F3-BCR-ABL P210 cells (- 84%) than untreated leukemia BALB/c mice. Furthermore, treatment of leukemia and non-leukemia mice with T2 combo showed no significant tissue alteration/damage according to the histopathological analysis of brain, heart, liver, kidney, and spleen samples; however, T2 combo significantly reduced the number of leukocytes in the bone marrow of treated leukemia mice. We conclude that the T2 combo specifically affects leukemia cells but no other tissue/organs. Therefore, we anticipate that the T2 combo might be a potential pro-oxidant combination for the treatment of leukemia patients.

Chronic Myelogenous Leukemia with Double Philadelphia Chromosome and Coexpression of p210 and p190 Fusion Transcripts.

The Philadelphia (Ph+) chromosome, t(9;22)(q34;q11.2), originates from a chimeric gene called BCR-ABL and is present in more than 90% of CML patients. Most patients with CML express the protein p210 BCR-ABL and, with a frequency lower than 5%, express rare isoforms, the main one being p190. In the transition from the chronic phase to the blast phase (BP), additional chromosomal abnormalities, such as the presence of the double Ph+ chromosome, are revealed. Of the 1132 patients analyzed via molecular biology in this study, two patients (0.17%) showed the co-expression of the p210 and p190 isoforms for the BCR-ABL transcript, with the concomitant presence of a double Ph+ chromosome, which was observed via conventional cytogenetics and confirmed by fluorescent in situ hybridization. The BCR-ABL/ABL% p210 and p190 ratio increased in these two patients from diagnosis to progression to blast crisis. To our knowledge, this is the first report in the literature of patients who co-expressed the two main BCR-ABL transcript isoforms and concomitantly presented Ph+ chromosome duplication. The evolution from the chronic phase to BP often occurs within 5 to 7 years, and, in this study, the evolution to BP was earlier, since disease-free survival was on average 4.5 months and overall survival was on average 9.5 months. The presence of the p190 transcript and the double Ph+ chromosome in CML may be related to the vertiginous progression of the disease.

Assessment of Carrot Callus as Biofactories of an Atherosclerosis Oral Vaccine Prototype.

Atherosclerosis is a pathology leading to cardiovascular diseases with high epidemiologic impact; thus, new therapies are required to fight this global health issue. Immunotherapy is a feasible approach to treat atherosclerosis and given that genetically engineered plants are attractive hosts for vaccine development; we previously proved that the plant cell is able to synthesize a chimeric protein called CTB:p210:CETPe, which is composed of the cholera toxin B subunit (CTB) as immunogenic carrier and target epitopes from the cholesteryl ester transfer protein (CETP461-476) and apolipoprotein B100 (p210). Since CTB:p210:CETPe was expressed in tobacco at sufficient levels to evoke humoral responses in mice, its expression in carrot was explored in the present study looking to develop a vaccine in a safe host amenable for oral delivery; avoiding the purification requirement. Carrot cell lines expressing CTB:p210:CETPe were developed, showing accumulation levels up to 6.1 µg/g dry weight. An immunoblot analysis revealed that the carrot-made protein is antigenic and an oral mice immunization scheme led to evidence on the immunogenic activity of this protein; revealing its capability of inducing serum IgG responses against p210 and CETP epitopes. This study represents a step forward in the development of an attractive oral low-cost vaccine to treat atherosclerosis.

Frecuencia de transcritos BCR/ABL p210 en 272 pacientes con leucemia mieloide crónica (LMC) en Bolivia / Frequency of p210 BCR-ABL transcripts in 272 Bolivian patients with chronic myeloid leukemia (CML)

INTRODUCCIÓN: existen dos formas principales del gen de fusión BCR/ABL, que involucra al exón 2 del gen ABL y a diferentes exones del gen BCR; los transcritos b2a2 o b3a2 codifican a la proteína p210, mientras que, el transcrito e1a2 codifica a la proteína p190. En Bolivia, no existe información sobre la frecuencia de estas isoformas (BCR/ABL quimérico) en pacientes con leucemia mieloide crónica (LMC). Objetivo.- Determinar la frecuencia de co-expresión de los transcritos p210 en pacientes con LMC de Bolivia. MATERIAL Y MÉTODO: se estudió 272 pacientes diagnosticados con LMC, entre julio del 1999 a agosto del 2015. Se realizó pruebas de RT-PCR (reverse transcriptase polymerase chain reaction) en muestras de médula ósea y sangre periférica de pacientes adultos y pediátricos con diagnóstico de LMC, positivos para algún tipo de reordenamiento BCR/ABL. RESULTADOS: la expresión del transcrito b2a2 se encontró en 96 pacientes (35,3%), el trascrito b3a2 en 154 casos (56,6%) y ambos transcritos en 22 pacientes (8,1%). Se realizó análisis de supervivencia, donde se observó que a los 5 años la tasa de sobrevida fue 64%; y la sobrevida libre de progresión 42%. También se observó que el tipo de transcrito no influye en la sobrevida total ni en la sobrevida libre de enfermedad. CONCLUSIÓN: se evidenció que no existen diferencias significativas de la expresión de los diferentes transcritos BCR/ABL de los pacientes estudiados en relación a otros estudios reportados.

There are two main forms of BCR/ABL fusion gene, involving exon 2 of ABL gene and different exons of the BCR gene, the transcripts b2a2 or b3a2 code for a p210 protein, and the transcript e1a2 code a p190 protein. In Bolivia, there is no information about the frequency of these isoforms of chimeric gene BCR/ABL in chronic myeloid leukemia (CML). The present study was designed to determine the frequency of co-expression of p210 transcripts in 272 patients with CML. It was conducted reverse transcriptase polymerase chain reaction (RT-PCR) tests in samples of bone marrow and peripheral blood of adult and pediatric patients with CML diagnosis, positive for some kind of BCR/ABL rearrangement. The transcript b2a2 was found in 96 (35,3%) patients; and b3a2 transcript in 154 (56.6%) cases; whereas, in 22 (8.1%) patients both transcripts were detected. Survival analysis was performed, it was observed that to 5 years the overall survival (OS) was 64%, and the progression free survival (PFS) was 42%. It was also observed that the type of transcript does not affect OS and PFS. Statistical analysis of our study, displayed no significant differences in the expression of different transcripts BCR/ABL of the Bolivian population, in relation to studies reported in other populations.

Desempenho de bovinos Nelore e cruzados Blonde dAquitaine x Nelore do nascimento ao desmame / Performance of Nellore and crossbred Blonde d"Aquitaine x Nellore from birth to weaning

This study aimed to evaluate the performance of Nellore and their crosses with Blonde d'Aquitaine (½Nellore + ½ Blonde d'Aquitaine) cattle from birth to weaning kept in grazing system in the State of Alagoas. 1,279 measures of birth weight (BW) and weaning weight adjusted to 210 days (P210) were analyzed for the period between 2005 and 2010. We used SAS® adopting a significance level of 5%. The average for BW and P210 were 31.60 kg and 158.66 kg respectively, for animals Nellore cattle, and 33.05 kg and 167.03 kg, for crossed animals. There was no interaction (P<0.05) between genetic group and sex, for any variable analyzed. We observed significant effects of genetic group, sex and season of birth (P<0.05) on birth weight. The genetic group and sex were significant on the P210. The effect of calving season was significant on birth weight, but no effect on P210 was observed, probably due to climatic variation found in the region. Males had higher body weights (P<0.05) showing sexual dimorphism. The Nellore cattle are superior to crossbred animals in all characteristics considered, providing even heavier calves at birth, without, however, presenting dystocic deliveries. The crossbred animals are also suitable in relation to large breed adaptation to climatic conditions and management which were submitted, making it an excellent option for crosses in the Northeast, in climatic conditions similar to this study.

Objetivou-se avaliar o desempenho produtivo de bovinos Nelore e suas cruzas com Blonde d'Aquitaine (½ Nelore + ½ Blonde d'Aquitaine) do nascimento ao desmame, mantidos em sistema de pastejo, no Estado de Alagoas. Foram analisadas 1.279 medidas de peso ao nascimento (PN) e peso à desmama ajustado para 210 dias (P210) referentes ao período entre os anos de 2005 e 2010. Utilizou-se o delineamento inteiramente casualizado, adotando-se um nível de significância de 5%. Os pesos médios para PN e P210 foram respectivamente 31,60kg e 158,66kg, para os animais Nelore, e 33,05kg e 167,03kg, para os animais cruzados. Não houve interação (P<0,05) entre grupo genético e sexo do animal, para nenhuma variável analisada. Foram observados efeitos significativos do grupo genético, sexo e época de nascimento (P<0,05) sobre PN. O grupo genético e o sexo foram significativos sobre o P210. O efeito de época de nascimento foi significativo no peso ao nascimento, mas não houve efeito no P210, provavelmente devido à variação climática verificada na região. Animais machos apresentaram pesos superiores (P<0,05) evidenciando o dimorfismo sexual. Os animais cruzados são superiores aos da raça Nelore em todas as características consideradas, proporcionando, inclusive, bezerros mais pesados ao nascimento, sem, no entanto, apresentar partos distócicos. Os animais cruzados também são adequados em relação à grande adaptação às condições climáticas e de manejo às quais foram submetidos, constituindo-se uma excelente opção para cruzamentos na região Nordeste, em condições ambientais semelhantes às deste estudo.

Desempenho de bovinos Nelore e cruzados Blonde dAquitaine x Nelore do nascimento ao desmame / Performance of Nellore and crossbred Blonde d"Aquitaine x Nellore from birth to weaning

This study aimed to evaluate the performance of Nellore and their crosses with Blonde d'Aquitaine (½Nellore + ½ Blonde d'Aquitaine) cattle from birth to weaning kept in grazing system in the State of Alagoas. 1,279 measures of birth weight (BW) and weaning weight adjusted to 210 days (P210) were analyzed for the period between 2005 and 2010. We used SAS® adopting a significance level of 5%. The average for BW and P210 were 31.60 kg and 158.66 kg respectively, for animals Nellore cattle, and 33.05 kg and 167.03 kg, for crossed animals. There was no interaction (P<0.05) between genetic group and sex, for any variable analyzed. We observed significant effects of genetic group, sex and season of birth (P<0.05) on birth weight. The genetic group and sex were significant on the P210. The effect of calving season was significant on birth weight, but no effect on P210 was observed, probably due to climatic variation found in the region. Males had higher body weights (P<0.05) showing sexual dimorphism. The Nellore cattle are superior to crossbred animals in all characteristics considered, providing even heavier calves at birth, without, however, presenting dystocic deliveries. The crossbred animals are also suitable in relation to large breed adaptation to climatic conditions and management which were submitted, making it an excellent option for crosses in the Northeast, in climatic conditions similar to this study.(AU)

Objetivou-se avaliar o desempenho produtivo de bovinos Nelore e suas cruzas com Blonde d'Aquitaine (½ Nelore + ½ Blonde d'Aquitaine) do nascimento ao desmame, mantidos em sistema de pastejo, no Estado de Alagoas. Foram analisadas 1.279 medidas de peso ao nascimento (PN) e peso à desmama ajustado para 210 dias (P210) referentes ao período entre os anos de 2005 e 2010. Utilizou-se o delineamento inteiramente casualizado, adotando-se um nível de significância de 5%. Os pesos médios para PN e P210 foram respectivamente 31,60kg e 158,66kg, para os animais Nelore, e 33,05kg e 167,03kg, para os animais cruzados. Não houve interação (P<0,05) entre grupo genético e sexo do animal, para nenhuma variável analisada. Foram observados efeitos significativos do grupo genético, sexo e época de nascimento (P<0,05) sobre PN. O grupo genético e o sexo foram significativos sobre o P210. O efeito de época de nascimento foi significativo no peso ao nascimento, mas não houve efeito no P210, provavelmente devido à variação climática verificada na região. Animais machos apresentaram pesos superiores (P<0,05) evidenciando o dimorfismo sexual. Os animais cruzados são superiores aos da raça Nelore em todas as características consideradas, proporcionando, inclusive, bezerros mais pesados ao nascimento, sem, no entanto, apresentar partos distócicos. Os animais cruzados também são adequados em relação à grande adaptação às condições climáticas e de manejo às quais foram submetidos, constituindo-se uma excelente opção para cruzamentos na região Nordeste, em condições ambientais semelhantes às deste estudo.(AU)