Integrative multi-kinase approach for the identification of potent antiplasmodial hits

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies.7CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP405996/2016-0; 400760/2014-2Sem informação2018/05926-2; 2017/02353-9; 2012/16525-2; 2017/18611-7; 2018/07007-4; 2013/13119-6; 2018/24878-9; 2015/20774-

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject

Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors.

Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Fatores associados ao consumo precoce de leite de vaca integral por crianças menores de um ano de idade

Objective: To assess the frequency and factors associated with the use of whole cow’s milk in children under one year old in the city of Fortaleza, Ceará. Methods: Cross-sectional analytical study conducted with 575 mothers of children under one year old living in the city of Fortaleza, Ceará. A semi-structured questionnaire was applied to collect sociodemographic data and information about the reproductive history of mothers, childbirth and the child. Results: The median age of mothers was 26.5 years, and 80.5% (n=463) of them had a household income of 1-5 minimum wages. The majority (83.2%, n=475) attended more than six prenatal consultations, but only 86.2% (n=494) said they had received information on breastfeeding. Among children who received other types of milk, 53.8% (n=191) consumed whole cow’s milk; of these, 31.7% (n=113) reported having received orientation from the pediatrician. Cow’s milk consumption was associated with maternal age (women under 18 years old (p=0.015)), income of less than five minimum wages (pObjetivo: Evaluar la frecuencia y los factores asociados al uso de la leche de la vaca integral en niños menores de un año de la ciudad de Fortaleza, Ceará. Métodos: Se realizó un estúdio transversal y analítico con 575 madres de niños menores de un año de edad residentes en Fortaleza, Ceará. Se aplicó un cuestionario semiestructurado para la recogida de datos sociodemográficos, la historia de reproducción de la madre, los datos del parto y del niño. Resultados: La mediana de la edad de las madres fue de 26,5 años con renta familiar entre 1 y 5 sueldos mínimos mensuales para el 80,5% (n=463). La mayoría (83,2%, n=475) realizo más de seis consultas de prenatal pero solo el 86,2% (n=494) se declaró haber recibido informaciones de la lactancia materna. Entre los niños que recibieron otro tipo de leche, el 53,8% (n=191) consumieron la leche de vaca integral y de estes el 31,7% (n=113) refieren haber recibido orientación del pediatra. El consumo de la leche de vaca estuvo relacionado a la edad materna (menores de 18 años de edad, (p=0,015), renta abajo de cinco sueldos mínimos (pObjetivo: Avaliar a frequência e fatores associados ao uso do leite de vaca integral nas crianças menores de um ano na cidade de Fortaleza, Ceará. Métodos: Realizou-se estudo transversal e analítico envolvendo 575 mães de crianças menores de um ano de idade residentes em Fortaleza, Ceará. Aplicou-se questionário semiestruturado para coleta de dados sociodemográficos, história reprodutiva da mãe, dados referentes ao parto e à criança. Resultados: A mediana de idade das mães foi de 26,5 anos, tendo 80,5% (n=463) renda familiar de 1 a 5 salários mínimos. A maior parte (83,2%, n=475) realizou mais de seis consultas de pré-natal, mas apenas 86,2% (n=494) declararam ter recebido informações sobre aleitamento materno. Entre as crianças que receberam outro tipo de leite, 53,8% (n=191) consumiram leite de vaca integral, e destas, 31,7% (n=113) referem ter recebido orientação do pediatra. O consumo do leite de vaca foi relacionado à idade materna (menores de 18 anos de idade, (p=0,015), renda inferior a cinco salários mínimos (

Anemia and anti-tuberculosis treatment outcome in persons with pulmonary tuberculosis: A multi-center prospective cohort study

Background: Tuberculosis (TB) remains a major plague of humanity. People with TB (PWTB) are commonly anemic. Here, we assessed whether the severity of anemia in PWTB prior to anti-TB treatment (ATT) was a risk factor for an unfavorable outcome. Methods: Patients ≥ 18 years old with culture-confirmed drug-susceptible pulmonary TB enrolled between 2015 and 2019 in a multi-center Brazilian cohort were followed for up to 24 months and classified according to anemia severity (mild, moderate, and severe), based on hemoglobin levels. A multinomial logistic regression model was employed to assess whether anemia was associated with unfavorable outcome (death, failure, loss to follow-up, regimen modification or relapse), compared to treatment success (cure or treatment completion). Results: Among 786 participants who met inclusion criteria, 441 (56 %) were anemic at baseline. Patients with moderate/severe anemia were more HIV-seropositive, as well as more symptomatic and had higher frequencies of unfavorable outcomes compared to the other groups. Moderate/severe anemia (adjusted OR [aOR]: 7.80, 95 %CI:1.34–45.4, p = 0.022) was associated with death independent of sex, age, BMI, HIV and glycemic status. Conclusion: Moderate/severe anemia prior to ATT was a significant risk factor for death. Such patients should be closely monitored given the high risk of unfavorable ATT outcomes