RESUMO
Water monitoring faces challenges that are driven by the infrastructure, protection, financial resources, science and innovation policies, among others. A modular, low-cost, fully open-source and small-sized Unmanned Surface Vessel (USV) called EMAC-USV (EMAC: Estación de Monitoreo Ambiental Costero), is proposed for monitoring bathymetry and water quality parameters (i.e. temperature, suspended solids concentration and hydrocarbon concentration) in complex water scenarios. A detailed description of each part of the platform as well as all electronic connections and functioning is presented.The field works were carried out in two small waste stabilization ponds and in a portion of the main tidal channel of the Bahía Blanca port. The EMAC-USV is the result of a cautious design, regarding the balancing performance, communications, payload capacity, among others.
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In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Antígenos CD19 , Intervalo Livre de Doença , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Estudos Prospectivos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Linfócitos TRESUMO
PURPOSE: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed. METHODS: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19. RESULTS: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts. CONCLUSION: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.
Assuntos
Antígenos CD19/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Projetos Piloto , Adulto JovemRESUMO
PURPOSE: To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS: Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS: The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18). CONCLUSION: Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD19/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Terapia de Salvação , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1ß were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1ß was associated with sepsis. This combination of IFNγ and IL1ß was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Sepse , Criança , Estado Terminal , Síndrome da Liberação de Citocina , Humanos , Receptores de Antígenos de Linfócitos T , Sepse/diagnósticoAssuntos
Transdiferenciação Celular , Imunoterapia/efeitos adversos , Linfoma de Célula do Manto/terapia , Segunda Neoplasia Primária/etiologia , Sarcoma/etiologia , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Reprogramação Celular/fisiologia , Terapia Combinada , Epigênese Genética/fisiologia , Epigenoma/imunologia , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Imunoterapia/métodos , Linfonodos/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Segunda Neoplasia Primária/diagnóstico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia , Transplante Autólogo/efeitos adversos , Células Tumorais CultivadasRESUMO
PURPOSE: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups. CONCLUSION: In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Idoso , Antígenos CD19/imunologia , Síndrome da Liberação de Citocina/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/imunologia , Recidiva , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/transplanteRESUMO
OBJECTIVES: Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome. DESIGN: Observational cohort. SETTING: Academic PICU. PATIENTS: Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course. CONCLUSIONS: Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.
Assuntos
Endotélio/fisiopatologia , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Síndrome do Desconforto Respiratório/epidemiologia , Sepse/epidemiologia , Sepse/fisiopatologia , Adolescente , Biomarcadores , Proteínas Sanguíneas/metabolismo , Moléculas de Adesão Celular/metabolismo , Criança , Pré-Escolar , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Mediadores da Inflamação , Estudos Longitudinais , Masculino , Escores de Disfunção Orgânica , Prognóstico , Síndrome do Desconforto Respiratório/sangue , Sepse/sangue , Fatores de TempoRESUMO
PURPOSE: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto JovemRESUMO
The threat of Foot and Mouth Disease (FMD) in South America has global economic implications and retaining a FMD Free status under the World Organization for Animal Health (OIE) remains a top priority. In Argentina the Servicio Nacional de Sanidad y Calidad Agroalimentaria (SENASA), the national service of agri-food health and quality, requires cattle located in the Pampean region of the Salado River basin to receive two foot-and-mouth disease (FMD) vaccinations per year, which results in one vaccination coinciding with beef cattle breeding season. While the vaccination program remains necessary, there is a growing concern amongst food animal veterinarians, that the overlap of FMD vaccination with the first 35 days of the breeding season is associated with early pregnancy loss (EPL). To address this concern, a preliminary randomized controlled trial t study was conducted to investigate the risk ratio (RR) of EPL in vaccinated, pregnant Aberdeen Angus heifers. Initially (Day 0), 858 heifers underwent fixed time-AI (FTAI). Subsequently, on day 33, following pregnancy diagnosis by transrectal ultrasonography pregnant heifers (nâ¯=â¯311) were randomly allocated to two treatment groups. Group 1 (162 animals) received an inactivated oil emulsion FMD vaccine, and Group 2 (149 animals) received a saline injection (control). On day 51 (18 days post vaccination), pregnancy status was re-evaluated by ultrasonography. The initial pregnancy rate (PR) on Day 33 was 58% (498/858 animals). On Day 51 (18 days post vaccination), PR in Group 1 was 96.3% (156/162 animals), and in Group 2 (control) was 98.6% (147/149 animals). The EPL in Group 1 was 3.7% (6/162 animals) and in Group 2 was 1.3% (2/149 animals). The RR of EPL in Group 1, compared to Group 2, was 2.8 (95% confidence interval: 0.6-13, p-value: 0.20). With such a wide range in confidence intervals and a p value of 0.20 a larger prospective study would be necessary to establish an unequivocally statistically significant link between heifer vaccination 33 days post FTAI and an increased risk of EPL.
Assuntos
Aborto Animal/epidemiologia , Doenças dos Bovinos/prevenção & controle , Febre Aftosa/prevenção & controle , Vacinação/veterinária , Aborto Animal/etiologia , Animais , Argentina/epidemiologia , Bovinos , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/etiologia , Feminino , Gravidez , Taxa de Gravidez , Vacinação/efeitos adversosAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia Adotiva , Terapia de Alvo Molecular , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Recidiva , Retratamento , Resultado do TratamentoRESUMO
OBJECTIVE: To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion. METHODS: We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor-modified T-cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity. RESULTS: Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31-60%) and was positively associated with higher CRS grade (p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)-2, IL-15, soluble IL-4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL-12 and soluble tumor necrosis factor receptor-1 within the first 3 days were seen in subjects with neurotoxicity. INTERPRETATION: Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537-546.
Assuntos
Antígenos CD19/metabolismo , Síndromes Neurotóxicas/diagnóstico , Síndromes Neurotóxicas/metabolismo , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/metabolismo , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Citocinas/metabolismo , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
Chimeric antigen receptor (CAR)-modified T cells are being investigated in many settings, including classical Hodgkin lymphoma (cHL). The unique biology of cHL, characterized by scant Hodgkin and Reed-Sternberg (HRS) cells within an immunosuppressive tumor microenvironment (TME), may pose challenges for cellular therapies directly targeting antigens expressed on HRS cells. We hypothesized that eradicating CD19+ B cells within the TME and the putative circulating CD19+ HRS clonotypic cells using anti-CD19-directed CAR-modified T cells (CART19) may indirectly affect HRS cells, which do not express CD19. Here we describe our pilot trial using CART19 in patients with relapsed or refractory cHL. To limit potential toxicities, we used nonviral RNA CART19 cells, which are expected to express CAR protein for only a few days, as opposed to CART19 generated by viral vector transduction, which expand in vivo and retain CAR expression. All 5 enrolled patients underwent successful manufacturing of nonviral RNA CART19, and 4 were infused with protocol-specified cell dose. There were no severe toxicities. Responses were seen, but these were transient. To our knowledge, this is the first CART19 clinical trial to use nonviral RNA gene delivery. This trial was registered at www.clinicaltrials.gov as #NCT02277522 (adult) and #NCT02624258 (pediatric).
Assuntos
Técnicas de Transferência de Genes , Doença de Hodgkin/terapia , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia , Adulto , Feminino , Doença de Hodgkin/genética , Doença de Hodgkin/imunologia , Humanos , Masculino , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologiaRESUMO
Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.
Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Desenho de Fármacos , Humanos , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , RatosRESUMO
Plant interactions with arbuscular mycorrhizal fungi have long attracted interest for their potential to promote more efficient use of mineral resources in agriculture. Their use, however, remains limited by a lack of understanding of the processes that determine the outcome of the symbiosis. In this study, the impact of host genotype on growth response to mycorrhizal inoculation was investigated in a panel of diverse maize lines. A panel of 30 maize lines was evaluated with and without inoculation with arbuscular mycorrhizal fungi. The line Oh43 was identified to show superior response and, along with five other reference lines, was characterized in greater detail in a split-compartment system, using 33 P to quantify mycorrhizal phosphorus uptake. Changes in relative growth indicated variation in host capacity to profit from the symbiosis. Shoot phosphate content, abundance of root-internal and -external fungal structures, mycorrhizal phosphorus uptake, and accumulation of transcripts encoding plant PHT1 family phosphate transporters varied among lines. Superior response in Oh43 is correlated with extensive development of root-external hyphae, accumulation of specific Pht1 transcripts and high phosphorus uptake by mycorrhizal plants. The data indicate that host genetic factors influence fungal growth strategy with an impact on plant performance.
Assuntos
Hifas/metabolismo , Micorrizas/metabolismo , Proteínas de Transporte de Fosfato/genética , Fósforo/metabolismo , Proteínas de Plantas/genética , Raízes de Plantas/microbiologia , Zea mays/genética , Zea mays/microbiologia , Biomassa , Regulação da Expressão Gênica de Plantas , Proteínas de Transporte de Fosfato/metabolismo , Desenvolvimento Vegetal , Proteínas de Plantas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The Angora goat populations in Argentina (AR), France (FR) and South Africa (SA) have been kept geographically and genetically distinct. Due to country-specific selection and breeding strategies, there is a need to characterize the populations on a genetic level. In this study we analysed genetic variability of Angora goats from three distinct geographical regions using the standardized 50k Goat SNP Chip. A total of 104 goats (AR: 30; FR: 26; SA: 48) were genotyped. Heterozygosity values as well as inbreeding coefficients across all autosomes per population were calculated. Diversity, as measured by expected heterozygosity (HE) ranged from 0.371 in the SA population to 0.397 in the AR population. The SA goats were the only population with a positive average inbreeding coefficient value of 0.009. After merging the three datasets, standard QC and LD-pruning, 15 105 SNPs remained for further analyses. Principal component and clustering analyses were used to visualize individual relationships within and between populations. All SA Angora goats were separated from the others and formed a well-defined, unique cluster, while outliers were identified in the FR and AR breeds. Apparent admixture between the AR and FR populations was observed, while both these populations showed signs of having some common ancestry with the SA goats. LD averaged over adjacent loci within the three populations per chromosome were calculated. The highest LD values estimated across populations were observed in the shorter intervals across populations. The Ne for the Angora breed was estimated to be 149 animals ten generations ago indicating a declining trend. Results confirmed that geographic isolation and different selection strategies caused genetic distinctiveness between the populations.
Assuntos
Variação Genética , Genética Populacional , Genoma , Cabras/genética , Polimorfismo de Nucleotídeo Único/genética , Animais , Argentina , Cromossomos de Mamíferos/genética , França , Marcadores Genéticos , Desequilíbrio de Ligação/genética , Densidade Demográfica , Análise de Componente Principal , Reprodutibilidade dos Testes , África do Sul , Estatística como AssuntoRESUMO
The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models.
Assuntos
Córtex Suprarrenal/imunologia , Aldosterona/imunologia , Imunomodulação/imunologia , Inflamação/imunologia , Modelos Imunológicos , Receptores de Mineralocorticoides/imunologia , Animais , Humanos , Fatores Imunológicos/imunologiaRESUMO
Over the past decade, the traditional description of astrocytes as being merely accessories to brain function has shifted to one in which their role has been pushed into the forefront of importance. Current views suggest that astrocytes:(1) are excitable through calcium fluctuations and respond to neurotransmitters released at synapses; (2) communicate with each other via calcium waves and release their own gliotransmitters which are essential for synaptic plasticity; (3) activate hundreds of synapses at once, thereby synchronizing neuronal activity and activating or inhibiting complete neuronal networks; (4) release vasoactive substances to the smooth muscle surrounding blood vessels enabling the coupling of circulation (blood flow) to local brain activity; and (5) release lactate in an activity-dependent manner in order to supply neuronal metabolic demand. In consequence, the role of astrocytes and astrocytic gliotransmitters is now believed to be critical for higher brain function and recently, evidence begins to gather suggesting that astrocytes are pivotal for learning and memory. All of the above are reviewed here while focusing on the role of astrocytes in memory and psychiatric disorders.
Assuntos
Astrócitos/metabolismo , Memória/fisiologia , Transtornos Mentais/patologia , Transtornos Mentais/fisiopatologia , Animais , HumanosRESUMO
CONTEXT: Non-falciparum malaria is less studied than Plasmodium falciparum malaria, both in endemic and non-endemic zones. PATIENTS AND METHOD: A retrospective study was made of the medical files of patients managed for attacks of malaria due to Plasmodium vivax or Plasmodium ovale, between 2000 and 2009, in two French military teaching hospitals. RESULTS: Seventy-five percent of attacks occurred after a stay in French Guiana, in the Comoros Archipelago, or in the Ivory Coast Republic. The most frequent symptoms two months after coming back were a flu-like syndrome with headaches, and occasional digestive symptoms, without any difference between the first attack and recurrence. One third of patients presented with anemia, 78% with thrombocytopenia, and 12% with liver dysfunction. DISCUSSION: This study was the most important made in France on imported non-falciparum malaria. Military patients and immigrants accounted for a majority of patients due to the specificity of military hospitals and local recruitment. Clinical and biological features were not specific and did not allow guiding the diagnosis. Diagnostic tools were less sensitive for P. ovale. CONCLUSION: Patient management could be optimized by more efficient diagnostic tools, specific guidelines for the diagnostic and therapeutic management, and a dedicated medical training for family practitioners as well as hospitals practice.