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Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features
No full text“Conselho
Nacional de Desenvolvimento Cient´ıfico e Tecnol´ogico”
(CNPq) for their personal scholarships (303247/2019-3 and
313350/2018-3, respectively).'e indiscriminate consumption of antimalarials against coronavirus disease-2019 emphasizes the longstanding clinical weapons
of medicines. In this work, we conducted a review on the antitumor mechanisms of aminoquinolines, focusing on the responses
and differences of tumor histological tissues and toxicity related to pharmacokinetics. 'is well-defined analysis shows similar
mechanistic forms triggered by aminoquinolines in different histological tumor tissues and under coexposure conditions, although
different pharmacological potencies also occur. 'ese molecules are lysosomotropic amines that increase the antiproliferative
action of chemotherapeutic agents, mainly by cell cycle arrest, histone acetylation, physiological changes in tyrosine
kinase metabolism, inhibition of PI3K/Akt/mTOR pathways, cyclin D1, E2F1, angiogenesis, ribosome biogenesis, triggering of
ATM-ATR/p53/p21 signaling, apoptosis, and presentation of tumor peptides. 'eir chemo/radiotherapy sensitization effects may
be an adjuvant option against solid tumors, since 4-aminoquinolines induce lysosomal-mediated programmed cytotoxicity of
cancer cells and accumulation of key markers, predominantly, LAMP1, p62/SQSTM1, LC3 members, GAPDH, beclin-1/Atg6,
α-synuclein, and granules of lipofuscin. Adverse effects are dose-dependent, though most common with chloroquine,
hydroxychloroquine, amodiaquine, and other aminoquinolines are gastrointestinal changes, blurred vision ventricular arrhythmias,
cardiac arrest, QTc prolongation, severe hypoglycemia with loss of consciousness, and retinopathy, and they are more
common with chloroquine than with hydroxychloroquine and amodiaquine due to pharmacokinetic features. Additionally,
psychological/neurological effects were also detected during acute or chronic use, but aminoquinolines do not cross the placenta
easily and low quantity is found in breast milk despite their long mean residence times, which depends on the coexistence of
hepatic diseases (cancer-related or not), first pass metabolism, and comedications. 'e low cost and availability on the world
market have converted aminoquinolines into “star drugs” for pharmaceutical repurposing, but a continuous pharmacovigilance is
necessary because these antimalarials have multiple modes of action/unwanted targets, relatively narrow therapeutic windows,
recurrent adverse effects, and related poisoning self-treatment. 'erefore, their use must obey strict rules, ethical and medical
prescriptions, and clinical and laboratory monitorin
Genetic Diversity and Potential Paths of Transmission of Mycobacterium bovis in the Amazon: The Discovery of M. bovis Lineage Lb1 Circulating in South America
No full textBovine tuberculosis (bTB) has yet to be eradicated in Brazil. Herds of cattle and
buffalo are important sources of revenue to people living in the banks of the Amazon
River basin. A better understanding of Mycobacterium bovis (M. bovis) populational
structure and transmission dynamics affecting these animals can significantly contribute
in efforts to improve their sanitary status. Herein, we sequenced the whole genome
of 22 M. bovis isolates (15 from buffalo and 7 from cattle) from 10 municipalities in
the region of the Lower Amazon River Basin in Brazil and performed phylogenomic
analysis and Single Nucleotide Polymorphism (SNP)-based transmission inference to
evaluate population structure and transmission networks. Additionally, we compared
these genomes to others obtained in unrelated studies in the Marajó Island (n = 15)
and worldwide (n = 128) to understand strain diversity in the Amazon and to infer
M. bovis lineages. Our results show a higher genomic diversity of M. bovis genomes
obtained in the Lower Amazon River region when compared to the Marajó Island,
while no significant difference was observed between M. bovis genomes obtained
from cattle and buffalo (p ≥ 0.05). This high genetic diversity is reflected by the
weak phylogenetic clustering of M. bovis from the Lower Amazon River region based
on geographic proximity and in the detection of only two putative transmission
clusters in the region. One of these clusters is the first description of inter-species
transmission between cattle and buffalo in the Amazon, bringing implications to the
bTB control program. Surprisingly, two M. bovis lineages were detected in our dataset,
namely Lb1 and Lb3, constituting the first description of Lb1 in South America.
Bovine tuberculosis (bTB) has yet to be eradicated in Brazil. Herds of cattle and
buffalo are important sources of revenue to people living in the banks of the Amazon
River basin. A better understanding of Mycobacterium bovis (M. bovis) populational
structure and transmission dynamics affecting these animals can significantly contribute
in efforts to improve their sanitary status. Herein, we sequenced the whole genome
of 22 M. bovis isolates (15 from buffalo and 7 from cattle) from 10 municipalities in
the region of the Lower Amazon River Basin in Brazil and performed phylogenomic
analysis and Single Nucleotide Polymorphism (SNP)-based transmission inference to
evaluate population structure and transmission networks. Additionally, we compared
these genomes to others obtained in unrelated studies in the Marajó Island (n = 15)
and worldwide (n = 128) to understand strain diversity in the Amazon and to infer
M. bovis lineages. Our results show a higher genomic diversity of M. bovis genomes
obtained in the Lower Amazon River region when compared to the Marajó Island,
while no significant difference was observed between M. bovis genomes obtained
from cattle and buffalo (p ≥ 0.05). This high genetic diversity is reflected by the
weak phylogenetic clustering of M. bovis from the Lower Amazon River region based
on geographic proximity and in the detection of only two putative transmission
clusters in the region. One of these clusters is the first description of inter-species
transmission between cattle and buffalo in the Amazon, bringing implications to the
bTB control program. Surprisingly, two M. bovis lineages were detected in our dataset,
namely Lb1 and Lb3, constituting the first description of Lb1 in South America. Most of the strains of this study (13/22) and all 15 strains of the Marajó Island carried no
clonal complex marker, suggesting that the recent lineage classification better describe
the diversity of M. bovis in the Amazon
O Brasil precisa do SUS: uma campanha pela vida
No full textFundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.
Intitulada acertadamente “O Brasil precisa do SUS”, a campanha é uma iniciativa da Frente pela Vida, que
reúne organizações de saúde, ciência e tecnologia, comunicação, educação e da sociedade civil. Em carta,
que lembra o tamanho da crise sanitária e as milhares de mortes por covid-19 no Brasil, elas ressaltam que a
desigualdade social serviu de terreno fértil para o vírus no país. “Ações relevantes de enfrentamento, que deveriam
ter sido lideradas pelo governo federal, foram sabotadas pelo presidente Jair Bolsonaro”, assinalam as entidades
no documento, pontuando a ausência de coordenação nacional, os testes armazenados sem uso e os recursos
financeiros retidos como exemplos de uma desorientação propositada que tem alimentado as mais altas taxas de
mortalidade e letalidade da covid-19 nas Américas, só comparáveis às de Estados Unidos, Peru e Chile
A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19
No full textBACKGROUND. Although convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data
from randomized controlled trials that support its efficacy are limited.
METHODS. We conducted a randomized, double-blind, controlled trial among adults hospitalized with severe and critical
COVID-19 at 5 sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized 2:1 to receive a single
transfusion of either convalescent plasma or normal control plasma. The primary outcome was clinical status at 28
days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the
intention-to-treat population.
RESULTS. Of 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to receive normal
control plasma. At 28 days, no significant improvement in the clinical scale was observed in participants randomized
to convalescent plasma (OR 1.50, 95% confidence interval [CI] 0.83–2.68, P = 0.180). However, 28-day mortality was
significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73
[24.6%], OR 0.44, 95% CI 0.22–0.91, P = 0.034). The median titer of anti–SARS-CoV-2 neutralizing antibody in infused
convalescent plasma units was 1:160 (IQR 1:80–1:320). In a subset of nasopharyngeal swab samples from Brazil that
underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.
CONCLUSION. In adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant
improvement in day 28 clinical status. However, convalescent plasma was associated with significantly improved survival. A
possible explanation is that survivors remained hospitalized at their baseline clinical status
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil
No full textBackground: Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis.
Methods: Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4 498 586 imputed single-nucleotide variants (SNVs). A genome-wide association study (GWAS) using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL) and chromatin interaction mapping was performed in Functional Mapping and Annotation (FUMA). Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay.
Results: Positional mapping identified 32 genomic loci associated with CL, none achieving genome-wide significance (P < 5 × 10-8). Lead SNVs at 23 loci occurred at protein coding or noncoding RNA genes, 15 with eQTLs for functionally relevant cells/tissues and/or showing differential expression in lesions. Of these, the 6 most plausible genetic risk loci were SERPINB10 (Pimputed_1000G = 2.67 × 10-6), CRLF3 (Pimputed_1000G = 5.12 × 10-6), STX7 (Pimputed_1000G = 6.06 × 10-6), KRT80 (Pimputed_1000G = 6.58 × 10-6), LAMP3 (Pimputed_1000G = 6.54 × 10-6), and IFNG-AS1 (Pimputed_1000G = 1.32 × 10-5). LAMP3 (Padjusted = 9.25 × 10-12; +6-fold), STX7 (Padjusted = 7.62 × 10-3; +1.3-fold), and CRLF3 (Padjusted = 9.19 × 10-9; +1.97-fold) were expressed more highly in CL biopsies compared to normal skin; KRT80 (Padjusted = 3.07 × 10-8; -3-fold) was lower. Multiple cis-eQTLs across SERPINB10 mapped to chromatin interaction regions of transcriptional/enhancer activity in neutrophils, monocytes, B cells, and hematopoietic stem cells. Those at IFNG-AS1 mapped to transcriptional/enhancer regions in T, natural killer, and B cells. The percentage of peripheral blood CD3+ T cells making antigen-specific interferon-γ differed significantly by IFNG-AS1 genotype.
Conclusions: This first GWAS for CL identified multiple genetic risk loci including a novel lead to understanding CL pathogenesis through regulation of interferon-γ by IFNG antisense RNA 1
Eosinophils are part of the granulocyte response in tuberculosis and promote host resistance in mice
No full textBruno B. Andrade, Artur T.L. Queiroz. Fundação Oswaldo Cruz. Instituto Gonçalo Muniz. Salvador, BA, Brasil.Andrea C. Bohrer (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Inflammation and Innate Immunity Unit. Bethesda, MD, United States of America.); Ehydel Castro (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Inflammation and Innate Immunity Unit. Bethesda, MD, United States of America.); Zhidong Hu (Fudan University. Shanghai Public Health Clinical Center. Department of Scientific Research. Shanghai, China / Fudan University. Shanghai Emerging and Re-emerging Infectious Disease Institute. Tuberculosis Center. Shanghai, China.); Artur T. L. Queiroz (The KAB Group / Multinational Organization Network Sponsoring Translational and Epidemiological Research. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.); Claire E. Tocheny (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Inflammation and Innate Immunity Unit. Bethesda, MD, United States of America.); Maike Assmann (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Inflammation and Innate Immunity Unit. Bethesda, MD, United States of America.); Shunsuke Sakai (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. T Lymphocyte Biology Section. Bethesda, MD, United States of America.); Christine Nelson (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. T Lymphocyte Biology Section. Bethesda, MD, United States of America.); Paul J. Baker (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Inflammation and Innate Immunity Unit. Bethesda, MD, United States of America.); Hui Ma (Fudan University. Shanghai Public Health Clinical Center. Department of Scientific Research. Shanghai, China / Fudan University. Shanghai Emerging and Re-emerging Infectious Disease Institute. Tuberculosis Center. Shanghai, China.); Lin Wang (Fudan University. Shanghai Emerging and Re-emerging Infectious Disease Institute. Tuberculosis Center. Shanghai, China / Fudan University. Shanghai Public Health Clinical Center. Department of Thoracic Surgery. Shanghai, China.); Wen Zilu (Fudan University. Shanghai Emerging and Re-emerging Infectious Disease Institute. Tuberculosis Center. Shanghai, China / Fudan University. Shanghai Public Health Clinical Center. Department of Thoracic Surgery. Shanghai, China.); Elsa du Bruyn (University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa.); Catherine Riou (University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa.); Keith D. Kauffman (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. T Lymphocyte Biology Section. Bethesda, MD, United States of America.); Tuberculosis Imaging Program (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of Intramural Research. Tuberculosis Imaging Program. Bethesda, MD, United States of America.); Ian N. Moore (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Comparative Medicine Branch. Infectious Disease Pathogenesis Section. Bethesda, MD, United States of America.); Franca Del Nonno (Istituto Di Ricovero e Cura a Carattere Scientifico. National Institute for Infectious Diseases "L. Spallanzani". Pathology Unit. Rome, Italy.); Linda Petrone (Istituto Di Ricovero e Cura a Carattere Scientifico. Department of Epidemiology and Preclinical Research National Institute for Infectious Diseases. Translational Research Unit. Rome, Italy.); Delia Goletti (Istituto Di Ricovero e Cura a Carattere Scientifico. Department of Epidemiology and Preclinical Research National Institute for Infectious Diseases. Translational Research Unit. Rome, Italy.); Adrian R. Martineau (University College London. Institute of Immunity and Transplantation. London, United Kingdom.); David M. Lowe (University College London. Institute of Immunity and Transplantation. London, United Kingdom.); Mark R. Cronan (Max Planck Institute for Infection Biology. In Vivo Cell Biology of Infection Unit. Berlin, Germany / Duke University School of Medicine. Department of Molecular Genetics and Microbiology. Durham, NC, United States of America.); Robert J. Wilkinson (University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / Imperial College London. Department of Infectious Diseases. London, United Kingdom.); Clifton E. Barry, III (University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Tuberculosis Research Section. Bethesda, MD, United States of America.); Laura E. Via (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of Intramural Research. Tuberculosis Imaging Program. Bethesda, MD, United States of America / National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Tuberculosis Research Section. Bethesda, MD, United States of America.); Daniel L. Barber (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. T Lymphocyte Biology Section. Bethesda, MD, United States of America.); Amy D. Klion (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. Human Eosinophil Section. Bethesda, MD, United States of America.); Bruno B. Andrade (The KAB Group / Multinational Organization Network Sponsoring Translational and Epidemiological Research. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.); Yanzheng Song (Fudan University. Shanghai Emerging and Re-emerging Infectious Disease Institute. Tuberculosis Center. Shanghai, China / Fudan University. Shanghai Public Health Clinical Center. Department of Thoracic Surgery. Shanghai, China.); Ka-Wing Wong (Fudan University. Shanghai Public Health Clinical Center. Department of Scientific Research. Shanghai, China / Fudan University. Shanghai Emerging and Re-emerging Infectious Disease Institute. Tuberculosis Center. Shanghai, China.); Katrin D. Mayer-Barber (National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Clinical Immunology and Microbiology. Inflammation and Innate Immunity Unit. Bethesda, MD, United States of America).Division of Intramural Research, National Institute of Allergy and Infectious Diseases and the National Natural Science Foundation of China (grant no. 81770010 to K.-W. Wong)National Institutes of Health (grant no. U01AI115940)Wellcome Trust (grant nos. 104803 and 203135)Cancer Research UK, UK Research and Innovation, and Wellcome Trust
(FC0010218)National Council for Scientific and Technological Development (senior fellowship)Intramural Research Program of the Oswaldo Cruz Foundation, BrazilHost resistance to Mycobacterium tuberculosis (Mtb) infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. An influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, using complementary genetic models of eosinophil deficiency, we demonstrate that in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice
Resumo do Boletim InfoGripe: semana epidemiológica (SE) 33 2021
No full textSemana epidemiológica 33: 15/08/2021 à 21/08/2021.O presente boletim é referente a análises com base nos dados inseridos no Sivep-gripe até o dia 23/08/2021. Apresentamos análises nacional, por região geopolítica, por regional baseada em perfil de atividade, e por UF, relatando o nível relativo ao plano de contingência, zona no canal endêmico e nível de atividade semanal para os dados de SRAG, SRAG por Influenza, e óbitos de SRAG por Influenza
Optimization and validation of an alternative method of residual moisture for quality control of lyophilized Measles, Mumps and Rubella vaccine
No full textOs autores externos submeteram sua publicação para apresentação de trabalho no evento “International Symposium on Immunobiologicals”, que foi coordenado e organizado pelo Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), da Fundação Oswaldo Cruz
Aniba rosaeodora (Var. amazonica Ducke) Essential Oil: Chemical Composition, Antibacterial, Antioxidant and Antitrypanosomal Activity
No full textAniba rosaeodora is one of the most widely used plants in the perfumery industry, being used
as medicinal plant in the Brazilian Amazon. This work aimed to evaluate the chemical composition
of A. rosaeodora essential oil and its biological activities. A. rosaeodora essential oil presented linalool
(93.60%) as its major compound. The A. rosaeodora essential oil and linalool showed activity against
all the bacteria strains tested, standard strains and marine environment bacteria, with the lower
minimum inhibitory concentration being observed for S. aureus. An efficient antioxidant activity
of A. rosaeodora essential oil and linalool (EC50: 15.46 and 6.78 µg/mL, respectively) was evidenced
by the inhibition of the 2,2-azinobis- (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical. The
antitrypanosomal activity of A. rosaeodora essential oil and linalool was observed at high concentra tions against epimatigote forms (inhibitory concentration for 50% of parasites (IC50): 150.5 ± 1.08
and 198.6 ± 1.12 µg/mL, respectively), and even higher against intracellular amastigotes of T. cruzi
(IC50: 911.6 ± 1.15 and 249.6 ± 1.18 µg/mL, respectively). Both A. rosaeodora essential oil and
linalool did not exhibit a cytotoxic effect in BALB/c peritoneal macrophages, and both reduced nitrite
levels in unstimulated cells revealing a potential effect in NO production. These data revealed the
pharmacological potential of A. rosaeodora essential oil and linalool, encouraging further studies
HIV‑1 molecular diversity in Brazil unveiled by 10 years of sampling by the national genotyping network
No full textCNPq (406510/2018-0)NIH Office of AIDS Research (OAR)HIV-1 has diversifed into several subtypes and recombinant forms that are heterogeneously spread around the world. Understanding the distribution of viral variants and their temporal dynamics can help to design vaccines and monitor changes in viral transmission patterns. Brazil has one of the largest HIV-1 epidemics in the western-world and the molecular features of the virus circulating in the country are still not completely known. Over 50,000 partial HIV-1 genomes sampled between 2008 and 2017 by the Brazilian genotyping network (RENAGENO) were analyzed. Sequences were fltered by quality, duplicate sequences per patient were removed and subtyping was performed with online tools and molecular phylogeny. Association between patients’ demographic data and subtypes were performed by calculating the relative risk in a multinomial analysis and trends in subtype prevalence were tested by Pearson correlation. HIV-1B was found to be the most prevalent subtype throughout the country except in the south, where HIV-1C prevails. An increasing trend in the proportion of HIV-1C and F1 was observed in several regions of the country, while HIV-1B tended to decrease. Men and highly educated individuals were more frequently infected by HIV-1B and non-B variants were more prevalent among women with lower education. Our results suggest that socio-demographic factors partially segregate HIV-1 diversity in Brazil while shaping viral transmission networks. Historical events could explain a preferential circulation of HIV-1B among men who have sex with men (MSM) and non-B variants among heterosexual individuals. In view of an increasing male/female ratio of AIDS cases in Brazil in the last 10–15 years, the decrease of HIV-1B prevalence is surprising and suggests a greater penetrance of non-B subtypes in MSM transmission chains