Tem sido sugerido que a periodização do treinamento de força (TF) é uma forma de se otimizar as adaptações induzidas pelo TF. O objetivo do presente estudo foi verificar o efeito de diferentes modelos de TF periodizados (PER) e não periodizado (NPER) nas adaptações funcionais, morfológicas e moleculares da musculatura esquelética. Trinta e quatro indivíduos fisicamente ativos (idade= 24,6 ±5,4 anos) foram divididos aleatoriamente aos grupos controle (C), não periodizado (GNP), periodizado linear (GPL) e periodizado ondulado (GPO) e submetidos a 12 semanas de treinamento. As medidas de força dinâmica máxima (1RM) e área de secção transversa muscular (ASTM) foram feitas nos momentos pré-treinamento, pós seis-semanas e pós 12-semanas. Biópsias musculares foram realizadas em quatro momentos diferentes, pré-treinamento, 24-horas após a primeira sessão de treinamento, 24-horas e 168-horas após a última sessão de treinamento. Após as seis semanas, os grupos GNP e GPO aumentaram os valores de 1RM, (17,0 ± 8,7%, p<0,0001 e 12,9 ± 9,9%, p< 0,01, respectivamente). Após as 12 semanas, os grupos GNP, GPL e o GPO aumentaram os valores de 1RM com relação aos valores pré-teste, (19,5 ± 13,2%, p<0,0001; 17,9 ± 13,7%, p<0,0001; e 20,4 ± 9,0%, p < 0,0001, respectivamente). Todos os grupos experimentais demonstraram ganhos significantes na hipertrofia muscular após seis (5,1 ± 2,7%, p < 0,0001) e doze semanas (9,5 ± 4,5% p < 0,0001) quando comparados aos valores iniciais. Adicionalmente, o grupo GPL foi o único que demonstrou aumentos na hipertrofia muscular entre as semanas seis e doze foi o GPL (6,4%, p<0,0001). Com relação a expressão proteica conteúdo total e fosoforilada, nenhuma das proteínas selecionadas apresentou diferença significante com relação aos valores pré-treinamento. Esses dados sugerem que quando o volume total é equalizado, os modelos PER e NPER empregados em TF são eficientes em promover ganhos na força e na hipertrofia muscular / It has been suggested that periodized regimens in strength training (ST) might optmize the training-induced adaptations. The purpose of current study was investigate the effects of different periodized (PER) and non-periodized (NPER) regimens on functional, morphological and molecular adaptations of skeletal muscle. Thirty four participants (age=24,6 ±5,4 years) were random allocated into four groups: control (C), non-periodized (GNP), linear periodized (GPL) and undulating periodized (GPO) and underwent 12 weeks of training, twice a week. Maximum dynamic strength (1RM) and quadriceps cross-sectional area (CSA) were evaluated at baseline and after six and 12 weeks. Muscle samples were obtained before, 24 hours after first ST session and 24 and 168 hours after the last training sessions. Only groups GNP (17.0 ± 8.7%, p<0.0001) and GPO (12.9 ± 9.9%, p< 0.01) increased 1RM after six weeks. After 12 weeks all groups increased their 1RM from pre-to-post test (19.5 ± 13.2%; p<0.0001), (17.9 ± 13.7%; p<0.0001) and (20.4 ± 9.0%; p < 0.0001) for GNP, GPL and GPO, respectively. All experimental groups increased quadriceps CSA after six (5.1 ± 2.7%, p < 0.0001) and 12 weeks (9.5 ± 4.5% p < 0.0001). Furthermore, only GPL significantly increased quadriceps CSA between six and 12 weeks (6.4%, p<0.0001). There were no significant changes in the selected proteins investigated. These results suggest that PER and NPER seem to induce similar muscle strength and hypertrophic responses in the volume load equated condition

Chronic Myeloid Leukemia is a kind of blood cancer with around 1 incidence per 100 000 persons/year. After the development of an effective treatment, imatinib, in the late 1990:s, the survival percentage has increased drastically. The high survival has turned the attention to different kinds of treatment responses, which in turn are good prognostic factors to future health status. In this thesis, the focus is on whether or not the patient has achieved a so called major molecular response after 12 month, or not. More precisely, the aim is to find prognostic factors to the 12 month response. In order to find prognostic factors for this binary response variable, a multivariate logistic regression analysis is conducted, with the goal of finding a parsimonious logistic model that describes the data. The analysis is done from a merged dataset from three earlier studies. The prognostic factors in the final model are treatment, 3 month response, and enlarged spleen. However, the residual analysis indicates that the model is incomplete, implying that further research needs to be done.

EGFR TKIs are standard therapy for advanced NSCLC. In order to define their role in early disease, we implemented a phase II trial of neoadjuvant gefitinib in clinical stage I NSCLC. Tumour shrinkage was seen in 43% of patients, with 11% achieving RECIST partial response (PR). Analysis of molecular markers showed EGFR TKD mutations in 17% of cases, being the only associated with PR. For the first time we defined the histopathological response of NSCLC to these agents, characterized by reduction in tumour cellularity and proliferative index as well as presence of non-mucinous BAC histology. Clinical PR tumours also presented large areas of stromal fibrosis with presence of focal residual tumour. In a characterization of intracellular signalling response, EGFR dephosphorylation in the residues Y1068 and Y1173 was not concordant and only the former was significantly reduced. pAkt Ser473/Akt and Thr308/Akt ratios were significantly reduced but observed among both, clinical responders and resistant patients. Interestingly, reduction in pEGFR Y1068 was significantly associated with increase in tumour cellularity (p=0.047), Ki-67 index (p=0.018) and tumour growth (p=0.019) with a residual perinuclear localization been detected, suggesting a novel mechanism of resistance involving receptor internalization. Finally, we determined that the EGFR protein remains stable up to one hour of post resection ischemia but two to three tumour samples are necessary for an adequate tumour representation. Furthermore, EGFR cytoplasmic compartment presented the best association with clinical response in our cohort. Taking all together, we were able to generate the first clinical trial exploring the use of an EGFR TKI in early NSCLC, characterizing for the first time the histopathological and signalling responses to these agents with an evidence of a potential novel mechanism of resistance. Finally, we observed that multiple samples collection for an adequate tumour representation, and assessment of the cytoplasmic compartment, are warrant.

EGFR TKIs are standard therapy for advanced NSCLC. In order to define their role in early disease, we implemented a phase II trial of neoadjuvant gefitinib in clinical stage I NSCLC. Tumour shrinkage was seen in 43% of patients, with 11% achieving RECIST partial response (PR). Analysis of molecular markers showed EGFR TKD mutations in 17% of cases, being the only associated with PR. For the first time we defined the histopathological response of NSCLC to these agents, characterized by reduction in tumour cellularity and proliferative index as well as presence of non-mucinous BAC histology. Clinical PR tumours also presented large areas of stromal fibrosis with presence of focal residual tumour. In a characterization of intracellular signalling response, EGFR dephosphorylation in the residues Y1068 and Y1173 was not concordant and only the former was significantly reduced. pAkt Ser473/Akt and Thr308/Akt ratios were significantly reduced but observed among both, clinical responders and resistant patients. Interestingly, reduction in pEGFR Y1068 was significantly associated with increase in tumour cellularity (p=0.047), Ki-67 index (p=0.018) and tumour growth (p=0.019) with a residual perinuclear localization been detected, suggesting a novel mechanism of resistance involving receptor internalization. Finally, we determined that the EGFR protein remains stable up to one hour of post resection ischemia but two to three tumour samples are necessary for an adequate tumour representation. Furthermore, EGFR cytoplasmic compartment presented the best association with clinical response in our cohort. Taking all together, we were able to generate the first clinical trial exploring the use of an EGFR TKI in early NSCLC, characterizing for the first time the histopathological and signalling responses to these agents with an evidence of a potential novel mechanism of resistance. Finally, we observed that multiple samples collection for an adequate tumour representation, and assessment of the cytoplasmic compartment, are warrant.

Tem sido sugerido que a periodização do treinamento de força (TF) é uma forma de se otimizar as adaptações induzidas pelo TF. O objetivo do presente estudo foi verificar o efeito de diferentes modelos de TF periodizados (PER) e não periodizado (NPER) nas adaptações funcionais, morfológicas e moleculares da musculatura esquelética. Trinta e quatro indivíduos fisicamente ativos (idade= 24,6 ±5,4 anos) foram divididos aleatoriamente aos grupos controle (C), não periodizado (GNP), periodizado linear (GPL) e periodizado ondulado (GPO) e submetidos a 12 semanas de treinamento. As medidas de força dinâmica máxima (1RM) e área de secção transversa muscular (ASTM) foram feitas nos momentos pré-treinamento, pós seis-semanas e pós 12-semanas. Biópsias musculares foram realizadas em quatro momentos diferentes, pré-treinamento, 24-horas após a primeira sessão de treinamento, 24-horas e 168-horas após a última sessão de treinamento. Após as seis semanas, os grupos GNP e GPO aumentaram os valores de 1RM, (17,0 ± 8,7%, p<0,0001 e 12,9 ± 9,9%, p< 0,01, respectivamente). Após as 12 semanas, os grupos GNP, GPL e o GPO aumentaram os valores de 1RM com relação aos valores pré-teste, (19,5 ± 13,2%, p<0,0001; 17,9 ± 13,7%, p<0,0001; e 20,4 ± 9,0%, p < 0,0001, respectivamente). Todos os grupos experimentais demonstraram ganhos significantes na hipertrofia muscular após seis (5,1 ± 2,7%, p < 0,0001) e doze semanas (9,5 ± 4,5% p < 0,0001) quando comparados aos valores iniciais. Adicionalmente, o grupo GPL foi o único que demonstrou aumentos na hipertrofia muscular entre as semanas seis e doze foi o GPL (6,4%, p<0,0001). Com relação a expressão proteica conteúdo total e fosoforilada, nenhuma das proteínas selecionadas apresentou diferença significante com relação aos valores pré-treinamento. Esses dados sugerem que quando o volume total é equalizado, os modelos PER e NPER empregados em TF são eficientes em promover ganhos na força e na hipertrofia muscular / It has been suggested that periodized regimens in strength training (ST) might optmize the training-induced adaptations. The purpose of current study was investigate the effects of different periodized (PER) and non-periodized (NPER) regimens on functional, morphological and molecular adaptations of skeletal muscle. Thirty four participants (age=24,6 ±5,4 years) were random allocated into four groups: control (C), non-periodized (GNP), linear periodized (GPL) and undulating periodized (GPO) and underwent 12 weeks of training, twice a week. Maximum dynamic strength (1RM) and quadriceps cross-sectional area (CSA) were evaluated at baseline and after six and 12 weeks. Muscle samples were obtained before, 24 hours after first ST session and 24 and 168 hours after the last training sessions. Only groups GNP (17.0 ± 8.7%, p<0.0001) and GPO (12.9 ± 9.9%, p< 0.01) increased 1RM after six weeks. After 12 weeks all groups increased their 1RM from pre-to-post test (19.5 ± 13.2%; p<0.0001), (17.9 ± 13.7%; p<0.0001) and (20.4 ± 9.0%; p < 0.0001) for GNP, GPL and GPO, respectively. All experimental groups increased quadriceps CSA after six (5.1 ± 2.7%, p < 0.0001) and 12 weeks (9.5 ± 4.5% p < 0.0001). Furthermore, only GPL significantly increased quadriceps CSA between six and 12 weeks (6.4%, p<0.0001). There were no significant changes in the selected proteins investigated. These results suggest that PER and NPER seem to induce similar muscle strength and hypertrophic responses in the volume load equated condition

<p>Human actions and the resultant global warming are leading to considerable environmental changes that are negatively impacting marine ecosystems and their biodiversity. Luidia clathrata, a starfish species, is essential to the marine ecosystem, and understanding its sensitivity to stressors can help predict its future adaptations and role in the reef ecosystem. The study involved subjecting L. clathrata to thermal stress by incrementally raising the temperature by 1°C each day for a period of seven days. Physiological responses were evaluated on two separate occasions: day 1, which corresponded to the acute stress response, and day 7, which corresponded to the chronic stress response. The results showed a minor increase in phagocytic activity during acute thermal stress, but a significant decrease during chronic exposure. Although there was a slight decrease in total coelomic plasma protein during acute thermal stress, it significantly increased during post-chronic exposure. The amputated starfish avoided using the injured arm when righting themselves, indicating the development of neurosensory potential. Total cell count increased slightly in all stressed groups during acute stress but decreased after prolonged exposure to stressors. The mortality rate of the temperature-stressed groups was 33%, indicating that prolonged exposure to temperatures exceeding expected future temperatures could be harmful to L. clathrata. To support the hypothesis at the molecular level, RNA/DNA ratios and Heat shock protein gene 90, a molecular marker for cellular stress, were studied. Although no significant differences were observed in transcriptomic level, the temperature-stressed group showed slightly upregulated hsp90 gene expression. The findings indicate that L. clathrata responds to stress similarly to vertebrates, highlighting the potential impact of climate change on marine ecosystems. This study provides a baseline for comprehending the stress response of starfish, and further research is recommended with a larger sample size and over a more extended period. It is interesting to note that the gonad and body wall extracts of starfish exhibit significant inhibitory activity against various tested pathogens. The findings suggest that starfish extracts may have potential medicinal uses as antimicrobial agents. However further research is needed to understand the mechanisms of action behind these inhibitory activities and to identify the specific compounds responsible for them.</p>

<p>Sea urchins are fascinating marine creatures belonging to the phylum Echinodermata that serve as an essential ecological component and hold promise as a prospective source of therapeutics. However, sudden environmental changes, such as global warming and marine pollution, are placing significant stress on these organisms. To maintain natural resources and exploit sea urchins commercially, researchers are investigating aquaculture as a solution.</p> <p>This investigation discloses the physiological and immunological effects of physical and chemical stressors on one of the most common edible species of sea urchin, <em>Arbacia punctulata</em>. The study employed an elevated temperature as a physical stressor (1°C/day), lipopolysaccharides (LPS) inoculation as a chemical stressor (4µg/ml/day), and a combination of both LPS and elevated temperature as combined stressors. The results demonstrated a significant alteration in the total and differential coelomocyte count in the LPS-stressed group (p<0.05) and combined stressed group (p<0.05) followed by abnormal behavioral activity compared to those of control. Additionally, exposure to acute LPS exposure (at day 1 and day 3) and combined stressors led to an increase in phagocytic capacity (p<0.05) and lysozyme activity (p<0.05). Chronic exposure to LPS and combined stressors resulted in a decrease in gonadosomatic index (p<0.05, at day 10) and lysozyme activity (at day 7). A significant increase in coelomic fluid (CF) protein (p<0.05)was observed in the temperature-stressed group on days 5 and 10, while the combined stressed group had significantly more CF protein on days 1, 5, 7, and 10. An upregulation of Nf-kB gene expression was also observed (p>0.05) in temperature stressed group.  </p> <p>The study also revealed that sea urchins contain bioactive compounds that protect against external and internal injury, cell death, and body wall extract of sea urchin exhibited high antioxidant activity(p<0.05). Furthermore, it confirmed the antibacterial activity (p<0.05) of sea urchin (<em>Arbacia punctulata </em>and<em> Lytechinus variegatus</em>) body wall and coelomic fluid (cell-free plasma) extracts against ten pathogenic bacteria. The ethyl acetate body wall extract of both sea urchin species demonstrated higher inhibitory activity against the pathogenic bacteria tested. Overall sea urchin has potentials to meet the demand of food and medicine. </p>

Dentre os vários tipos de leucemia, destaca-se a Leucemia Mielóide Crônica (LMC), um distúrbio mieloproliferativo em que ocorre a translocação entre o gene BCR no cromossomo 22 e o gene ABL1 no cromossomo 9. Essa translocação cria um cromossomo conhecido como Philadelphia (t 9,22)(q34;q11), ou Ph+, e a consequente formação de um produto único de proteínas BCR-ABL1. Essa proteína tem atividade de quinase constitutiva e impulsiona a proliferação descontrolada de células tronco hematopoiéticas. O surgimento de uma nova classe farmacológica no início dos anos 2000 - os inibidores de tirosina quinases, revolucionou o tratamento e o prognóstico da LMC, permitindo que esse câncer fosse tratado praticamente como uma doença crônica, com farmacoterapia oral. A droga de estréia dessa classe, o Mesilato de Imatinib, foi desenvolvida através de modelagem molecular para ser alvo-específica, mas apesar do desenvolvimento exitoso, após o início da comercialização, foram observadas falhas na ação em determinados pacientes. Há evidências de que a avaliação da relação entre a dose de imatinibe (e seus níveis sanguíneos) e a eficácia do tratamento medida através das respostas Hematológica, Citogenética e Molecular, seja uma forma de realizar o ajuste da dose reduzindo efeitos colaterais e custo do tratamento. No presente estudo foram avaliadas as concentrações séricas de imatinib, Cmin e Cmax, em 51 pacientes com Leucemia Mielóide Crônica, dos quais 33 atingiram Resposta Molecular Maior em até 12 meses de tratamento, 11 levaram mais que 12 meses para antingir, e 7 não atingiram. As concentrações séricas obtidas desses pacientes indicaram que no grupo que atingiu RMM em até 12 meses, os valores de vale (Cmin) se apresentaram com mediana de 889.2 ng/mL (721.9 e 1202.4 para primeiro e terceiro quartis respectivamente), sendo que o grupo que levou mais de 12 meses para atingir RMM, a concentração mediana observada foi de 611.0 ng/mL (493.0 e 816.0 para primeiro e terceiro quartis respectivamente), sendo essa diferença estatisticamente significativa (p < 0.05). Dessa forma demonstrou-se a importância do monitoramento das concentrações séricas de imatinib para o ajuste da dose e para a gestão do tratamento na mudança para segunda geração de inibidores de tirosina quinase. Através da análise comparativa dos dados populacionais estudados, observou-se não haver correlação significativa entre as concentrações séricas e índice de massa corpórea (IMC), peso, idade ou sexo / Among the various types of leukemia, Chronic Myeloid Leukemia (CML) stands out as a myeloproliferative disorder in which translocation occurs between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. This translocation creates a chromosome known as Philadelphia (t 9,22) (q34; q11), or Ph +, and the consequent formation of a unique BCR-ABL1 protein product. This protein has constitutive kinase activity and drives the uncontrolled proliferation of hematopoietic stem cells. The launch of a new pharmacological class in the early 2000s - the tyrosine kinases inhibitors, revolutionized the treatment and prognosis of CML, allowing that cancer to be treated virtually as a chronic disease with oral pharmacotherapy. The newbie drug of this class, Imatinib Mesylate, was developed through molecular modeling to be target-specific, but despite the successful development, after the beginning of marketing, certain patients presented some failures in the response. There is an evidence that an assessment of the relationship between a dose of Imatinib (and its blood levels) and the efficacy of treatment from its Hematologic, Cytogenetic and Molecular Responses, is a really effective way to perform dose adjustment reducing side effects and cost of treatment. In the present study, the serum concentrations of Imatinib, Cmin and Cmax were evaluated in 51 patients with chronic myeloid leukemia, of which 33 reached major molecular response in up to 12 months of treatment, 10 took more than 12 months to achieve it, and 7 did not reach that. The serum concentrations obtained from those patients indicated that in the group that reached Major Molecular Response (MMR) within 12 months, the trough level (Cmin) presented a median of 889.2 ng / mL (721.9 and 1202.4 for first and third quartiles, respectively), and the group which took more than 12 months to reach MMR, the median concentration observed was 611.0 ng / mL (493.0 and 816.0 for the first and third quartiles respectively), and this difference was statistically significant (p < 0.05). Thus, the importance of monitoring serum imatinib concentrations for dose adjustment and treatment management in switching to second-generation tyrosine kinase inhibitors has been demonstrated. Through the comparative analysis of the population data, there was no significant correlation between serum concentrations and body mass index (BMI), weight, age or gender

Dentre os vários tipos de leucemia, destaca-se a Leucemia Mielóide Crônica (LMC), um distúrbio mieloproliferativo em que ocorre a translocação entre o gene BCR no cromossomo 22 e o gene ABL1 no cromossomo 9. Essa translocação cria um cromossomo conhecido como Philadelphia (t 9,22)(q34;q11), ou Ph+, e a consequente formação de um produto único de proteínas BCR-ABL1. Essa proteína tem atividade de quinase constitutiva e impulsiona a proliferação descontrolada de células tronco hematopoiéticas. O surgimento de uma nova classe farmacológica no início dos anos 2000 - os inibidores de tirosina quinases, revolucionou o tratamento e o prognóstico da LMC, permitindo que esse câncer fosse tratado praticamente como uma doença crônica, com farmacoterapia oral. A droga de estréia dessa classe, o Mesilato de Imatinib, foi desenvolvida através de modelagem molecular para ser alvo-específica, mas apesar do desenvolvimento exitoso, após o início da comercialização, foram observadas falhas na ação em determinados pacientes. Há evidências de que a avaliação da relação entre a dose de imatinibe (e seus níveis sanguíneos) e a eficácia do tratamento medida através das respostas Hematológica, Citogenética e Molecular, seja uma forma de realizar o ajuste da dose reduzindo efeitos colaterais e custo do tratamento. No presente estudo foram avaliadas as concentrações séricas de imatinib, Cmin e Cmax, em 51 pacientes com Leucemia Mielóide Crônica, dos quais 33 atingiram Resposta Molecular Maior em até 12 meses de tratamento, 11 levaram mais que 12 meses para antingir, e 7 não atingiram. As concentrações séricas obtidas desses pacientes indicaram que no grupo que atingiu RMM em até 12 meses, os valores de vale (Cmin) se apresentaram com mediana de 889.2 ng/mL (721.9 e 1202.4 para primeiro e terceiro quartis respectivamente), sendo que o grupo que levou mais de 12 meses para atingir RMM, a concentração mediana observada foi de 611.0 ng/mL (493.0 e 816.0 para primeiro e terceiro quartis respectivamente), sendo essa diferença estatisticamente significativa (p < 0.05). Dessa forma demonstrou-se a importância do monitoramento das concentrações séricas de imatinib para o ajuste da dose e para a gestão do tratamento na mudança para segunda geração de inibidores de tirosina quinase. Através da análise comparativa dos dados populacionais estudados, observou-se não haver correlação significativa entre as concentrações séricas e índice de massa corpórea (IMC), peso, idade ou sexo / Among the various types of leukemia, Chronic Myeloid Leukemia (CML) stands out as a myeloproliferative disorder in which translocation occurs between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. This translocation creates a chromosome known as Philadelphia (t 9,22) (q34; q11), or Ph +, and the consequent formation of a unique BCR-ABL1 protein product. This protein has constitutive kinase activity and drives the uncontrolled proliferation of hematopoietic stem cells. The launch of a new pharmacological class in the early 2000s - the tyrosine kinases inhibitors, revolutionized the treatment and prognosis of CML, allowing that cancer to be treated virtually as a chronic disease with oral pharmacotherapy. The newbie drug of this class, Imatinib Mesylate, was developed through molecular modeling to be target-specific, but despite the successful development, after the beginning of marketing, certain patients presented some failures in the response. There is an evidence that an assessment of the relationship between a dose of Imatinib (and its blood levels) and the efficacy of treatment from its Hematologic, Cytogenetic and Molecular Responses, is a really effective way to perform dose adjustment reducing side effects and cost of treatment. In the present study, the serum concentrations of Imatinib, Cmin and Cmax were evaluated in 51 patients with chronic myeloid leukemia, of which 33 reached major molecular response in up to 12 months of treatment, 10 took more than 12 months to achieve it, and 7 did not reach that. The serum concentrations obtained from those patients indicated that in the group that reached Major Molecular Response (MMR) within 12 months, the trough level (Cmin) presented a median of 889.2 ng / mL (721.9 and 1202.4 for first and third quartiles, respectively), and the group which took more than 12 months to reach MMR, the median concentration observed was 611.0 ng / mL (493.0 and 816.0 for the first and third quartiles respectively), and this difference was statistically significant (p < 0.05). Thus, the importance of monitoring serum imatinib concentrations for dose adjustment and treatment management in switching to second-generation tyrosine kinase inhibitors has been demonstrated. Through the comparative analysis of the population data, there was no significant correlation between serum concentrations and body mass index (BMI), weight, age or gender