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Venetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, however the emergence of resistant cells is a current complication. We and others, previously reported that the activation of CLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B cell lymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We here studied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showed an aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, surviving cells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustained resistance to a second treatment with the drug. Interestingly, the spleen tyrosine kinase (SYK) inhibitor entospletinib, and the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor idelalisib, reduced T cell activation, impaired the generation of leukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight a novel combination to overcome resistance to venetoclax in CLL.
Assuntos
Leucemia Linfocítica Crônica de Células B , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Sulfonamidas , Microambiente TumoralRESUMO
Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1ß in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.
Assuntos
Carbolinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Quimiocina CCL19/imunologia , Quimiocina CCL19/metabolismo , Quimiocina CCL21/imunologia , Quimiocina CCL21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Cultura Primária de Células , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/imunologiaRESUMO
The combination of two microextraction techniques (dispersive liquid-liquid microextraction [DLLME] and magnetic dispersive microsolid phase extraction [MDMSPE]) was developed and reported for atrazine and simazine preconcentration from wastewater samples. The proposal methodology involved the use of magnetite supports functionalized with different alkyl or phenyl groups. The magnetic adsorbents were synthesized by the solvothermal method assisted by microwave, characterized, and used in the sample preconcentration of atrazine and simazine. The method validation included parameters such as the wastewater matrix effect, repeatability, and recovery. The analyte separation and quantification were performed by high-performance liquid chromatography with ultraviolet detection (HPLC-DAD). Parameters, such as the polarity and mass of magnetic solids and pH, were evaluated to provide better extraction performance. The highest recoveries (> 95%) were obtained with 50 mg of the phenyl group support (CS2) at pH 5, using 5 mL of the sample and carbon tetrachloride and methanol, as extraction and dispersive solvents, respectively. The lowest limits of detection (LOD) achieved were 13.16 and 13.86 ng L-1, and the limits of quantification (LOQ) were 43.89 and 46.19 ng L-1 for simazine and atrazine, respectively, with repeatability (expressed as %RSD) below 5% in all cases. The developed method is simple, easy, and low cost for the analysis of two herbicides potentially dangerous for environmental and human health. Graphical abstract.
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Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients. This effect could not be ascribed to Syk-inhibition given that we show that T cells from CLL patients do not express Syk protein. Interestingly, ζ-chain-associated protein kinase (ZAP)-70 phosphorylation was diminished by both inhibitors upon TCR stimulation on T cells. In addition, we found that both agents reduced macrophage-mediated phagocytosis of rituximab-coated CLL cells. Overall, these results suggest that in CLL patients treated with R406 or GS-9973 T cell functions, as well as macrophage-mediated anti-tumor activity of rituximab, might be impaired. The potential consequences for CLL-treated patients are discussed.
Assuntos
Indazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Macrófagos/imunologia , Oxazinas/farmacologia , Pirazinas/farmacologia , Piridinas/farmacologia , Quinase Syk/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Proteína-Tirosina Quinase ZAP-70/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fagocitose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Rituximab/farmacologia , Linfócitos T/imunologiaRESUMO
Bacillus anthracis protective antigen (PA) is a well known and relevant immunogenic protein that is the basis for both anthrax vaccines and diagnostic methods. Properly folded antigenic PA is necessary for these applications. In this study a high level of PA was obtained in recombinant Escherichia coli. The protein was initially accumulated in inclusion bodies, which facilitated its efficient purification by simple washing steps; however, it could not be recognized by specific antibodies. Refolding conditions were subsequently analyzed in a high-throughput manner that enabled nearly a hundred different conditions to be tested simultaneously. The recovery of the ability of PA to be recognized by antibodies was screened by dot blot using a coefficient that provided a measure of properly refolded protein levels with a high degree of discrimination. The best refolding conditions resulted in a tenfold increase in the intensity of the dot blot compared to the control. The only refolding additive that consistently yielded good results was L-arginine. The statistical analysis identified both cooperative and negative interactions between the different refolding additives. The high-throughput approach described in this study that enabled overproduction, purification and refolding of PA in a simple and straightforward manner, can be potentially useful for the rapid screening of adequate refolding conditions for other overexpressed antigenic proteins.
Assuntos
Antígenos de Bactérias/biossíntese , Antígenos de Bactérias/imunologia , Bacillus anthracis/imunologia , Bacillus anthracis/metabolismo , Modelos Moleculares , Redobramento de ProteínaAssuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Ativação Linfocitária/efeitos dos fármacos , Proteínas de Neoplasias , Sulfonamidas/farmacologia , Quinase Syk , Linfócitos T , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Rituximab/farmacologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/imunologia , Quinase Syk/metabolismo , Linfócitos T/imunologia , Linfócitos T/patologiaAssuntos
Leucemia Linfocítica Crônica de Células B/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Biomarcadores , Proliferação de Células/genética , Sobrevivência Celular/genética , Progressão da Doença , Feminino , Humanos , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de SinaisRESUMO
Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.
Assuntos
Imunoglobulinas Intravenosas/imunologia , Imunomodulação , Leucemia Linfocítica Crônica de Células B/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Imunoglobulinas Intravenosas/farmacologia , Imunomodulação/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/sangue , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Sulfonamidas/farmacologiaRESUMO
This CIRSE Standards of Practice document provides best practices for the safe administration of procedural sedation and analgesia for interventional radiology procedures in adults. The document is aimed at health professionals involved in the provision of sedation and analgesia during interventional radiology procedures. The document has been developed by a writing group consisting of physicians with internationally recognised expertise in interventional radiology, and analgesia and sedation.
Assuntos
Analgesia/normas , Sedação Consciente/normas , Manejo da Dor/métodos , Radiologia Intervencionista/métodos , Adulto , HumanosRESUMO
OBJECTIVE: To present the results of metabolic control in patients with type 2 Diabetes Mellitus from a private clinic in Northern Mexico. METHODS: This cross-sectional study used retrospective data obtained from electronic records from a private outpatient clinic at the end of 2018. Inclusion criteria were a diagnosis of T2DM and age ≥ 18 years. Baseline characteristics (age, gender, drug use) were reported. The achievement of glycated hemoglobin goals was established as <7%. RESULTS: A total of 3820 patients were evaluated. Their mean age was 59.86 years (+/-15.01). Of the population, 46.72% were men, and 53.28% were women. Glycated hemoglobin goals were adequate in 1872 (54%) patients. There were 3247 patients (85%) treated with oral medications, of which 1948 (60%) reported glycated hemoglobin less than 7%. Insulin use was reported in 573 (15%) patients, with 115 (20%) reporting glycated hemoglobin less than 7%. The most frequently used basal insulin was glargine in 401 (70%) patients. CONCLUSIONS: Our findings are clearly higher than the control rate reported by our national health surveys of 25% with glycated hemoglobin < 7%, but similar to that reported in other countries. The most commonly used therapeutic scheme was the combination of oral hypoglycemic agents. The percentage of cases that include insulin in their treatment was lower. Clinical inertia to insulin initiation and intensification has been defined as an important cause of this problem.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina Glargina/administração & dosagem , Insulina/administração & dosagem , Adulto , Idoso , Estudos Transversais , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas , Humanos , Masculino , México , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
COVID-19 (SARS-CoV-2 virus) pandemic was recently declared by the WHO as a global health emergency. A group of interventional radiology senior experts developed a consensus document for infection control and management of patients with COVID-19 in interventional radiology (IR) departments. This consensus statement has been brought together at short notice with the help of different protocols developed by governmental entities and scientific societies to be adapted to the current reality and needs of IR Departments. Recommendations are the specific strategies to follow in IR departments, preventive measures and regulations, step by step for donning and doffing personal protective equipment, specific IR procedures which can not be delayed, and aerosol-generating procedures in IR with COVID-19 patients. It is advisable with this document to be adapted to local workplace policies.
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Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Controle de Infecções/normas , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Radiologia Intervencionista/métodos , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Surtos de Doenças , Humanos , Equipamento de Proteção Individual , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Radiologia Intervencionista/instrumentação , SARS-CoV-2RESUMO
PURPOSE: To evaluate the hemolysin effect by ileal loop model produced by Vibrio cholerae O1 strains, compared with the cellular lysis or cytotoxic activity (CA) observed in cell culture. METHOD: We studied nine V. cholerae O1 strains, obtained during the Mexican outbreak of cholera (1990-1993), which had CA in Vero and CHO cells. Hemolysin was monitored with the hemolysis test. Titers of CA were calculated by CD50, and the association between CA and cholera toxin (CT) production was discarded by means of neutralization tests using an anti-CT polyclonal antibody. The CT production was measured with ELISA test. The LAL assay was performed in order to study relationships between the CA and bacterial lipopolysaccharide. Strains with CA were evaluated in rabbit and rat ileal loop models; hemorrhagic fluid was also measured. Tissues from ileal loop were included in paraffin to detect intestinal epithelial damage. RESULTS: The hemolysin CA was not neutralized with the anti-CT polyclonal antibody. However, the associated factor of CA was heat labile. CA in cell cultures was not related to the bacterial lipopolysaccharide. The ileal loop test exhibited the presence of hemorrhagic tissue with inflammation. CONCLUSION: The V. cholerae O1 strains isolated were able to secrete hemolysin which, in turn, caused CA in cell cultures and produced the hemorrhagic and inflammatory effects observed in the ileal loop of rabbit and rat models.
Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/farmacologia , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/farmacologia , Vibrio cholerae O1/metabolismo , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Toxina da Cólera/metabolismo , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Hemólise/efeitos dos fármacos , Lipopolissacarídeos/metabolismo , Coelhos , Ratos , Ratos Wistar , Células VeroRESUMO
PURPOSE: We analyzed the scientific production of members of the Spanish Society of Vascular and Interventional Radiology (SERVEI) from 2010 to 2015. MATERIALS AND METHODS: We retrospectively analyzed the indexed scientific productivity of all SERVEI members for the last 6 years as measured by bibliometric indexes. Different databases were used (e.g., PubMed, Scopus, Web of Knowledge) to retrieve the total number of publications, number of citations, and h-index. Every article was assigned the impact factor of its publication year and its corresponding quartile according to Journal Citation Reports. The relationships between all of these parameters and the Spanish region, the gender and age of the interventional radiologists (IRs), and their connection to the university environment were also studied. RESULTS: A total of 519 scientific articles from 247 SERVEI members working in 118 Spanish hospitals were included, an average of 0.3 articles per interventionist/year. Most of the manuscripts were published in impact journals (52.2%) and placed in the lowest quartile (Q4). Navarre, Aragon, and Catalonia were the regions with the highest publication rate during the period studied (1.7, 0.92, and 0.6 publications per interventionist/year, respectively). Only 57 articles (12.6%) were published in 11 of the 125 journals under the category of Radiology, Nuclear Medicine, and Medical Imaging according to JCR. CONCLUSIONS: The scientific production of the Spanish IRs in the last 6 years is difficult to interpret. However, more than 50% of IRs published one article in the last 6 years. Finally, it would be advisable to repeat this study over a period of time in order to compare.
Assuntos
Bibliometria , Publicações Periódicas como Assunto , Editoração , Radiologia Intervencionista , Sociedades Médicas , Bases de Dados Factuais , Humanos , Fator de Impacto de Revistas , Estudos Retrospectivos , EspanhaRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive chronic disease associated with severe microvascular and macrovascular complications. Our aim is to assess the real world effectiveness of SGT" inhibitors in achieving metabolic therapeutic goals. METHODS: A retrospective, observational study. Inclusion criteria for patients were a previous diagnosis of type 2 diabetes mellitus, age > 18 years, patients receiving either dapagliflozin 10 mg and/or canagliflozin 300 mg. We excluded pregnant patients, patients with type 1 diabetes mellitus and acute metabolic complications of diabetes. Patients included in the analysis were enrolled in a health plan at least 6 months prior to the index date (baseline period) and in the 6 months following the index date (follow-up period). Achievement of glycated hemoglobin goals were established as <7%. RESULTS: We screened 2870 Mexican patients; 288 (10.03% received SGLT2 inhibitors). Mean age for both groups of patients was 57.68 ± 11.06 years. The dapagliflozin control rate was 19.56% and the canagliflozin control rate 18.96%. Monotherapy with SGLT2 inhibitors was used in 21 patients (6.25%). Overall HbA1c goals were met in 56 patients (19.44%) with similar results with dapagliflozin or canagliflozin. The combination of SGLT2 inhibitors and sulfonylureas had the highest control rate (30.30%) compared to other regimens. Monotherapy was present in 6.25%. Insulin requirement was associated with poor control (2.8% vs. 18.05%, P < 0.05, 95% CI [0.07, 0.84]). Combination therapy with DPP4 inhibitors was associated with better control (P < 0.05, 95% CI, [1.10, 3.92]). CONCLUSION: No difference between the drugs was observed. Real-world effectiveness data of SGLT2 inhibitors show that the percentage of patients reaching metabolic goals is low. SLGT2 inhibitors were used more frequently as combined therapy.
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SUMMARY OBJECTIVE To present the results of metabolic control in patients with type 2 Diabetes Mellitus from a private clinic in Northern Mexico, METHODS This cross-sectional study used retrospective data obtained from electronic records from a private outpatient clinic at the end of 2018. Inclusion criteria were a diagnosis of T2DM and age ≥ 18 years. Baseline characteristics (age, gender, drug use) were reported. The achievement of glycated hemoglobin goals was established as <7%. RESULTS A total of 3820 patients were evaluated. Their mean age was 59.86 years (+/-15.01). Of the population, 46.72% were men, and 53.28% were women. Glycated hemoglobin goals were adequate in 1872 (54%) patients. There were 3247 patients (85%) treated with oral medications, of which 1948 (60%) reported glycated hemoglobin less than 7%. Insulin use was reported in 573 (15%) patients, with 115 (20%) reporting glycated hemoglobin less than 7%. The most frequently used basal insulin was glargine in 401 (70%) patients. CONCLUSIONS Our findings are clearly higher than the control rate reported by our national health surveys of 25% with glycated hemoglobin < 7%, but similar to that reported in other countries. The most commonly used therapeutic scheme was the combination of oral hypoglycemic agents. The percentage of cases that include insulin in their treatment was lower. Clinical inertia to insulin initiation and intensification has been defined as an important cause of this problem.
RESUMO OBJETIVO Apresentar os resultados do controle metabólico de pacientes com Diabetes Mellitus tipo 2 em uma clínica privada no norte do México, MÉTODOS Este estudo transversal utilizou dados retrospectivos obtidos em prontuários eletrônicos de um ambulatório privado no final de 2018. Os critérios de inclusão foram o diagnóstico de DM2 e idade ≥ 18 anos. Características basais (idade, sexo, uso de drogas) foram relatadas. A realização de metas de hemoglobina glicada foi estabelecida como <7%. RESULTADOS Um total de 3820 pacientes foram avaliados. A média de idade foi de 59,86 anos (+/- 15,01). Da população, 46,72% eram homens e 53,28% eram mulheres. Objetivos de hemoglobina glicada foram adequados em 1872 (54%) pacientes. Havia 3247 pacientes (85%) tratados com medicamentos orais relatando em 1948 (60%) menos de 7%. O uso de insulina foi relatado em 573 (15%) pacientes, com 115 (20%) relatando menos de 7%. A insulina basal mais utilizada foi a glargina, em 401 (70%) pacientes. CONCLUSÕES Nossos resultados são claramente mais altos do que a taxa de controle relatada por nossos levantamentos nacionais de saúde de 25% com hemoglobina glicada <7%, mas semelhante à relatada em outros países. O esquema terapêutico mais utilizado foi a combinação de hipoglicemiantes orais. A porcentagem de casos que incluem insulina no tratamento foi menor. A inércia clínica à iniciação e intensificação da insulina tem sido definida como uma importante causa desse problema.
Assuntos
Humanos , Masculino , Feminino , Adulto , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Hemoglobinas Glicadas , Estudos Transversais , Estudos Retrospectivos , Quimioterapia Combinada , Insulina Glargina/administração & dosagem , México , Pessoa de Meia-IdadeRESUMO
The radiologic anatomy of the aortic bifurcation in the rabbit has received little study but it is important as this anatomical area is widely used in atherosclerosis research. Thirty rabbits were used to study the aortic bifurcation and subsequent branching patterns on arteriography. Fifteen different arteries were identified. Mean arterial diameters of 2.88 ± 0.7 and 2.27 ± 0.55 mm were obtained for the aorta and external iliac arteries, respectively. The cranial and middle aspects at the seventh lumbar vertebra (L7) were the most frequent anatomical landmarks (53.3% of the cases) for aortic and common iliac bifurcations, respectively. The caudal aspect of L6 was the most frequent origin (50% of the cases) for the median sacral artery. Deep circumflex iliac arteries originated from common iliac arteries and not the abdominal aorta in the rabbit, showing anatomical asymmetry in 73.3% of the cases. No gender disparity was found in the anatomical location of any of the arteries of the study. Knowledge of normal vascular landmarks for the aortic bifurcation as well as anatomical variations should be helpful to future experimental studies.
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Angiografia/métodos , Aorta Abdominal/anormalidades , Aorta Abdominal/anatomia & histologia , Artéria Ilíaca/anormalidades , Artéria Ilíaca/anatomia & histologia , Animais , Aorta Abdominal/diagnóstico por imagem , Feminino , Artéria Ilíaca/diagnóstico por imagem , Masculino , CoelhosRESUMO
INTRODUCCIÓN: Las metástasis cutáneas (MC) son un fenómeno poco frecuente en pacientes que padecen de cáncer de origen visceral, en mujeres se deben principalmente al cáncer de mama (CDM). Las MC se pueden presentar como manifestación de un cáncer avanzado o como signo de recidiva de un cáncer en remisión. La presentación clínica de un CDM en piel es muy variada, al estar presente es un indicador de enfermedad avanzada y , a su vez, de mal pronóstico, donde la variante clínica nodular es la más representativa. PRESENTACIÓN DEL CASO: Paciente femenina, 58 años. Con historia en 2005 de MC como primera manifestación de CDM. Presentó evolución satisfactoria y regresión de MC posterior a tratamiento con quimioterapia y radioterapia. Se resolvió quirúrgicamente, asociado a terapia hormonal, continuando en control ambulatorio. En 2018 consulta por lesión cutánea en pierna derecha, donde se constató además lesión cutánea mamaria izquierda. Se realizó biopsia de ambas lesiones que informó carcinoma epidermoide in situ en pierna derecha y metástasis dérmica de carcinoma ductal mamario con extensión intraepidérmica en zona mamaria izquierda y cervical ipsilateral. DISCUSIÓN: Las MC generalmente son precedidas por el diagnóstico de tumor mamario, rara vez son primera manifestación de él. De las MC cuya aparición es posterior al hallazgo de CDM, pueden observarse lesiones incluso al cabo de 10 años, lo que ha llevado a afirmar que el riesgo de enfermedad a distancia estará presente durante el resto de la vida. La presencia de MC por CDM implica generalmente amplia diseminación de la enfermedad, por lo tanto tener en cuenta este diagnóstico sería de gran ayuda en cuanto a oportunidad de tratamiento.
INTRODUCTION: Cutaneous metastases (MC) are a rare phenomenon in patients suffering from visceral cancer, in women they are mainly due to breast cancer (CDM). MC can occur as a manifestation of advanced cancer or as a sign of recurrence of a cancer in remission. The clinical presentation of a CDM in skin is very varied, being present is an indicator of advanced disease and, in turn, of poor prognosis, where the nodular clinical variant is the most representative. PRESENTATION OF THE CASE: Female patient, 58 years old. With history in 2005 of MC as the first manifestation of BC. After treatment with chemo and radiotherapy she presented satisfactory evolution and regression of CM. It was resolved later with surgery and hormonal therapy, continuing in ambulatory control. In 2018, the patient complained of a cutaneous lesion in the right leg. Physical exam also revealed a left mammary skin lesion. Biopsy was performed on both lesions. It reported carcinoma in situ in the right leg and dermal metastasis of mammary ductal carcinoma with intraepidermal extension in the left mammary and cervical area. DISCUSSION: CM are generally found after discovering the mammary tumor, they are rarely its first manifestation. As late manifestation of the disease, CM have been reported up to ten years later. The presence of MC by CDM generally implies a broad dissemination of the disease, taking into account this diagnosis could be of great help in terms of an opportunity for treatment.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Cutâneas/secundário , Neoplasias da Mama/patologia , Carcinoma de Células Escamosas , Metástase Neoplásica , Neoplasias Cutâneas/patologia , PrevalênciaRESUMO
Bacillus anthracis protective antigen (PA) is a well known and relevant immunogenic protein that is the basis for both anthrax vaccines and diagnostic methods. Properly folded antigenic PA is necessary for these applications. In this study a high level of PA was obtained in recombinant Escherichia coli. The protein was initially accumulated in inclusion bodies, which facilitated its efficient purification by simple washing steps; however, it could not be recognized by specific antibodies. Refolding conditions were subsequently analyzed in a high-throughput manner that enabled nearly a hundred different conditions to be tested simultaneously. The recovery of the ability of PA to be recognized by antibodies was screened by dot blot using a coefficient that provided a measure of properly refolded protein levels with a high degree of discrimination. The best refolding conditions resulted in a tenfold increase in the intensity of the dot blot compared to the control. The only refolding additive that consistently yielded good results was L-arginine. The statistical analysis identified both cooperative and negative interactions between the different refolding additives. The high-throughput approach described in this study that enabled overproduction, purification and refolding of PA in a simple and straightforward manner, can be potentially useful for the rapid screening of adequate refolding conditions for other overexpressed antigenic proteins.
El antígeno protector de Bacillus anthracis (protective antigen, PA) es una importante proteína inmunogénica, en la que se basan tanto las vacunas contra el ántrax/carbunclo como varios métodos diagnósticos. Para estas aplicaciones es esencial que el PA mantenga sus propiedades antigénicas, para lo cual debe estar correctamente plegado. En este estudio se obtuvieron altos niveles del PA en Escherichia coli recombinante. Inicialmente, la proteína se acumuló desnaturalizada en cuerpos de inclusión, lo que facilitó su eficiente purificación en simples pasos de lavado, pero no fue reconocida por anticuerpos específicos. Se analizaron las condiciones de replegado con un sistema de alto rendimiento, evaluando simultáneamente casi un centenar de condiciones diferentes. La recuperación de la capacidad del PA de ser reconocido por los anticuerpos se evaluó por dot blot utilizando un coeficiente que proporcionó una medida de los niveles de proteína correctamente plegada, con un alto grado de discriminación. Las mejores condiciones de renaturalización permitieron un aumento de diez veces en la intensidad de los dot blots con respecto del control. El único aditivo que produjo buenos resultados de forma constante fue la L-arginina. El análisis estadístico de las interacciones entre los diferentes aditivos de replegado permitió identificar tanto interacciones cooperativas como negativas. El enfoque de alto rendimiento descripto en este trabajo, que permitió la sobreproducción, purificación y plegado del PA de una manera sencilla y directa, puede ser potencialmente útil para el rápido screening de las condiciones adecuadas de replegado cuando se sobreexpresan otras proteínas antigénicas.
Assuntos
Redobramento de Proteína/efeitos dos fármacos , Anticorpos/análise , Antígenos/análise , Bacillus anthracis/efeitos dos fármacos , Bacillus anthracis/imunologia , Dobramento de Proteína/efeitos dos fármacosRESUMO
We investigated subcellular localization of total brain-derived neurotrophic factor (BDNF) mRNA (panBDNF) and its different 5' exon-specific transcripts in cultured hypothalamic neurons. Non-isotopic in situ hybridization (DIG-labeled exon-specific riboprobes) associated with immunocytochemical MAP2 or GFAP labeling was used for detection. We found that under basal conditions panBDNF mRNA was localized in neuronal soma and in primary dendritic processes. Transcripts I and II were weakly expressed in neuronal soma while transcripts IV and VI mRNA were strongly expressed. panBDNF mRNA and transcript VI mRNA were detected in proximal dendritic processes and in astrocytes. N-methyl-D: -aspartate (NMDA) treatment decreased the dendritic label of panBDNF and transcript VI mRNA. In contrast, MK-801 (NMDA antagonist) treatment extended the labeling of all the transcripts in dendrites while K(+) depolarization only extended the dendritic labeling of panBDNF and transcript VI mRNAs. These results suggest a NMDA-receptor dependent inhibitory mechanism for dendritic destination of BDNF transcripts in hypothalamic neurons.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Maleato de Dizocilpina/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Hipotálamo/citologia , N-Metilaspartato/farmacologia , Neurônios , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Células Cultivadas , Dendritos/genética , Dendritos/metabolismo , Embrião de Mamíferos , Éxons/genética , Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
La cirugía mínima invasiva constituye uno de los grandes avances de la medicina en las tres últimas décadas. La cirugía pediátrica no ha escapado a este progreso, y hoy en día son muchas las indicaciones de esta técnica en el niño. El nódulo pulmonar solitario se define como una lesión esférica rodeada por parénquima sano, no asociada a atelectasia y sin adenopatías mediastinales, Se reporta el caso deescolar femenino de 9 años de edad quien presentó evidencia radiológica de nódulo pulmonar solitario ubicado a nivel de la base del campo pulmonar derecho. Se realizó resección toracoscópica del mismo. Fueron descartadas patologías oncológicas, tuberculosis, micosis y enfermedades de depósito. Únicamente fue positiva la serología para Chlamydia pneumoniae (IgM), sin embargo, la pacientenunca presento clínica de infección respiratoria baja antes de su ingreso. La biopsia evidenció una lesión inflamatoria encapsulada inespecífica. Se concluye que la toracoscópia debe ser el método de primera elección ante cualquier lesión torácica y a cualquier edad enpediatría
Minimally invasive surgery constitutes one of the greatest advances of medicine in the last three decades. Pediatric surgery has not escaped this progress; in fact, nowadays there are many indications to perform this technique on children. Solitary pulmonary nodule is defined as a spherical lesion surrounded by healthy parenchyma, not associated with atelectasia and without mediastinallymphadenopathy. We present a nine-year-old girl, with radiological evidence of a solitary pulmonary nodule located at base of the right lung field. A thoracoscopic resection was performed. Oncological pathologies, tuberculosis, mycosis and deposit illnesses werediscarded. The only positive serology was for Chlamydia pneumoniae (IgM); however, the patient never presented clinical lower respiratory infection before her admission. The biopsy determined an encapsulated nonspecific inflammatory lesion. We conclude thatthoracoscopy should be the method of choice for any thoracic injury in children