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Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal hematological diseases associated with driver mutations in JAK2, CALR, and MPL genes. Moreover, several evidence suggests that chronic inflammation and alterations in stromal and immune cells may contribute to MPN's pathophysiology. We evaluated the frequency and the immunophenotype of peripheral blood monocyte subpopulations in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Peripheral blood monocytes from PV (n = 16), ET (n = 16), and MF (n = 15) patients and healthy donors (n = 10) were isolated and submitted to immunophenotyping to determine the frequency of monocyte subpopulations and surface markers expression density. Plasma samples were used to measure the levels of soluble CD163, a biomarker of monocyte activity. PV, ET, and MF patients presented increased frequency of intermediate and non-classical monocytes and reduced frequency of classical monocytes compared to controls. Positivity for JAK2 mutation was significantly associated with the percentage of intermediate monocytes. PV, ET, and MF patients presented high-activated monocytes, evidenced by higher HLA-DR expression and increased soluble CD163 levels. The three MPN categories presented increased frequency of CD56 +  aberrant monocytes, and PV and ET patients presented reduced frequency of CD80/86 +  monocytes. Therefore, alterations in monocyte subpopulations frequency and surface markers expression pattern may contribute to oncoinflammation and may be associated with the pathophysiology of MPN., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Postacute COVID-19 has become a relevant public health problem, and radiological and pulmonary function tests are tools that help physicians in decision-making. The objectives of this study are to characterize the findings and patterns on a chest radiograph (CXR) and computed tomography (CT) that are most important in the postacute phase and to evaluate how these changes correlate with clinical data, spirometry, and impulse oscillometry (IOS). This was a retrospective study of 29 patients who underwent CXR, CT, spirometry, and IOS. The inclusion criteria were age >18 years and persistent respiratory symptoms after four weeks. The exclusion criteria were radiological exams with low technical quality and non-COVID-19 acute lung diseases. The inferential analysis was carried out with the chi-square ( χ 2 ) or Fisher's exact test to evaluate the interrelationships between the clinical and COVID-19 variables according to spirometry, IOS, CT, and CXR. In our sample, 19 patients were women (65.5%). The predominance of abnormal spirometry was associated with CT's moderate/severe degree of involvement ( p  = 0.017; 69.2%, CI 95%: 44.1%-94.3%). There was no significant association between IOS and tomographic and radiographic parameters. A significant association was found between the classifications of the moderate/severe and normal/mild patterns on CT and CXRs ( p  = 0.003; 93.3%, CI 95%: 77.8%-100%). Patients with moderate/severe impairment on CXR were associated with a higher frequency of hospitalization ( p  = 0.033; 77.8%, CI 95%: 58.6%-97.0%) and had significantly more moderate/severe classifications in the acute phase than the subgroup with normal/mild impairment on CXR ( p  = 0.017; 88.9%, CI 95%: 74.4%-100%). In conclusion, the results of this study show that CXR is a relevant examination and may be used to detect nonspecific alterations during the follow-up of post-COVID-19 patients. Small airway disease is an important finding in postacute COVID-19 syndrome, and we postulate a connection between this pattern and the persistently low-level inflammatory state of the lung., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Roberto Mogami et al.)

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that expresses the Philadelphia chromosome and constitutively activated Bcr-Abl tyrosine kinase in hematopoietic progenitor cells. Bcr-Abl tyrosine-kinase inhibitors (TKI) do not definitively cure all CML patients. The efficacy of TKI is reduced in CML patients in the blastic phase-the most severe phase of the disease-and resistance to this drug has emerged. There is limited knowledge on the underlying mechanisms of disease progression and resistance to TKI beyond BCR-ABL1 , as well as on the impact of TKI treatment and disease progression on the metabolome of CML patients. The present study reports the metabolomic profiles of CML patients at different phases of the disease treated with TKI. The plasma metabolites from CML patients were analyzed using liquid chromatography, mass spectrometry, and bioinformatics. Distinct metabolic patterns were identified for CML patients at different phases of the disease and for those who were resistant to TKI. The lipid metabolism in CML patients at advanced phases and TKI-resistant patients is reprogrammed, as detected by analysis of metabolomic data. CML patients who were responsive and resistant to TKI therapy exhibited distinct enriched pathways. In addition, ceramide levels were higher and sphingomyelin levels were lower in resistant patients compared with control and CML groups. Taken together, the results here reported established metabolic profiles of CML patients who progressed to advanced phases of the disease and failed to respond to TKI therapy as well as patients in remission. In the future, an expanded study on CML metabolomics may provide new potential prognostic markers for disease progression and response to therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Almeida, Berzoti-Coelho, Toro, Cacemiro, Bassan, Barretto, Garibaldi, Palma, de Figueiredo-Pontes, Sorgi, Faciolli, Gardinassi and de Castro.)

We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8 + T cells. In vivo HMA treatment promotes CD8 + T cell tumor infiltration and suppresses tumor growth via CD8 + T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8 + T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8 + T cell subpopulations, increasing both the number and abundance of a granzyme B high , perforin high effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response., Competing Interests: Declaration of interests D.D.D.C. received research funds from Pfizer and Nektar Therapeutics. D.D.D.C. is a co-founder and shareholder of DNAMx, Inc. C.K. is employed by and owns stock, patents, and royalties with Roche. J.S. is a permanent scientific advisory board member for and owns stock in Surface Oncology., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis constitute a group of haematological diseases. The comprehensive assessment of signaling pathway activation in blood cells may aid the understanding of MPN pathophysiology. Thus, levels of post-translational protein modifications and total protein expression were determined in MPN patients and control leukocytes by using reverse-phase protein arrays (RPPA). Compared to control samples, p-SRC, p-CTNNB1, c-MYC, MCL-1, p-MDM2, BAX and CCNB1 showed higher expression in PV samples than controls. P-JAK2/JAK2 and pro-apoptotic BIM showed differential expression between JAK2 V617F-positive and -negative ET patients. Apoptosis, cancer and PI3K/AKT pathways proteins showed differential expression among the studied groups. For most of the proteins analyzed using Western-Blot and RPPA, RPPA showed higher sensitivity to detect subtle differences. Taken together, our data indicate deregulated protein expression in MPN patients compared to controls. Thus, RPPA may be a useful method for broad proteome analysis in MPN patients´ leukocytes.

Hippeastrum psittacinum, Amaryllidaceae, is used in traditional medicine as a purgative, aphrodisiac, and anticough remedy. The ethanol extract (EE) and alkaloid-rich fractions (ARF) from H. psittacinum bulbs were evaluated for their acetylcholinesterase (AChE) inhibition. The EE cytotoxic and anti-inflammatory effects in RAW 264.7 cells, and the neuroprotective and genotoxic activities in SH-SY5Y cells, were also estimated. Fifteen alkaloids were identified in the EE by gas chromatography-mass spectrometry. ARFs were less active for AChE inhibition than EE. The viability of both cell lines was higher than 70% with EE concentrations below 25 μg/mL. The EE decreased nitrite release in RAW cells stimulated with lipopolysaccharide, showing values of 83, 67, and 53% at 6.25, 12.5, and 25 μg/mL, respectively. Furthermore, the EE partially protected SH-SY5Y cells from hydrogen peroxide-mediated deleterious effects by approximately 50% at the same concentrations. The micronucleus assays showed that the extract caused chromosomal missegregation at concentrations above 12.5 μg/mL. The in silico analyses showed that some alkaloids presented properties of permeation of the blood-brain barrier and the intestine. Our findings present new evidence of the potential of H. psittacinum potential as an AChE inhibitor, as well as an anti-inflammatory and neuroprotective agent., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Efficient induction of effector and long-term protective antigen-specific CD8 + T memory response by vaccination is essential to eliminate malignant and pathogen-infected cells. Intracellular infectious bacteria, including Listeria monocytogenes , have been considered potent vectors to carry multiple therapeutic proteins and generate antigen-specific CD8 + T cell responses. Although the role of molecules involved in inflammatory cell death pathways, such as necroptosis (RIPK3-mediated) and pyroptosis (Caspase-1/11-mediated), as effectors of immune response against intracellular bacteria are relatively well understood, their contribution to the adjuvant effect of recombinant bacterial vectors in the context of antigen-specific CD8 + T cell response remained obscure. Therefore, we evaluated the impact of RIPK3 and Caspase-1/11 (Casp-1/11) individual and combined deficiencies on the modulation of antigen-specific CD8 + T cell response during vaccination of mice with ovalbumin - expressing L. monocytogenes (LM-OVA). We observed that Casp-1/11 but not RIPK3 deficiency negatively impacts the capacity of mice to clear LM-OVA. Importantly, both RIPK3 and Casp-1/11 are necessary for optimal LM-OVA-mediated antigen-specific CD8 + T cell response, as measured by in vivo antigen-specific CD8 + T cell proliferation, target cell elimination, and cytokine production. Furthermore, Casp-1/11 and Casp-1/11/RIPK3 combined deficiencies restrict the early initiation of antigen-specific CD8 + T cell memory response. Taken together, our findings demonstrate that RIPK3 and Casp-1/11 influence the quality of CD8 + T cell responses induced by recombinant L. monocytogenes vectors., (Copyright © 2020 Rana, Campos de Almeida, Paico Montero, Gonzales Carazas, Bortoluci, Sad and Amarante-Mendes.)

Background: The HER2 (human epidermal growth factor receptor-2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto-activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population., Methods: Polymorphism genotype was assessed through RFLP-PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi-squared or Fisher's exact test, respectively., Results: A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27-0.93, P = .036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki-67)., Conclusion: Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC., (© 2018 Wiley Periodicals, Inc.)

Background: Anacardium occidentale L phenolic lipid (LDT11) is used in traditional medicine as anti-inflammatory, astringent, antidiarrheal, anti-asthmatic and depurative. Phenolic derivatives, such as anacardic acid, extracted from cashew nut shell liquid (CNSL) have demonstrated biological and pharmacological properties, and its profile makes it a candidate for the development of new anti-inflammatory agents. The objective of the present study was to evaluate the anti-inflammatory profile of a derivative, synthesized from LDT11, on an in vitro cellular model., Methods: Organic synthesis of the phenolic derivative of CNSL that results in the hemi-synthetic compound LDT11. The cytotoxicity of the planned compound, LDT11, was analyzed in murine macrophages cell line, RAW264.7. The cells were previously treated with LDT11, and then, the inflammation was stimulated with lipopolysaccharide (LPS), in intervals of 6 h and 24 h. The analysis of the gene expression of inflammatory markers (TNFα, iNOS, COX-2, NF-κB, IL-1β and IL-6), nitric oxide (NO) dosage, and cytokine IL-6 were realized., Results: The results showed that the phenolic derivative, LDT11, influenced the modulatory gene expression. The relative gene transcripts quantification demonstrated that the LDT11 disclosed an immunoprotective effect against inflammation by decreasing genes expression when compared with cells stimulated with LPS in the control group. The NO and IL-6 dosages confirmed the results found in gene expression., Discussion: The present study evaluated the immunoprotective effect of LDT11. In addition to a significant reduction in the expression of inflammatory genes, LDT11 also had a faster and superior anti-inflammatory action than the commercial products, and its response was already evident in the test carried out six hours after the treatment of the cells., Conclusion: This study demonstrated LDT11 is potentially valuable as a rapid immunoprotective anti-inflammatory agent. Treatment with LDT11 decreased the gene expression of inflammatory markers, and the NO, and IL-6 production. When compared to commercial drugs, LDT11 showed a superior anti-inflammatory action.

Breast cancer represents a complex and heterogeneous disease that comprises distinct disease conditions, histological features, and clinical outcome. Since many years, it has been demonstrated as an association between HER2 amplification and poor prognosis, because its overexpression is associated with an aggressive phenotype of breast tumor cells. A significant proportion of cases have developed resistance to the current therapies available. Consequently, new prognostic markers are urgently needed to identify patients who are at the highest risk for developing metastases. During the past decade, new insights provided valuable knowledge regarding mechanisms underlying the dynamic interplayed between immune cells and tumor progression. It has been shown that the presence of a lymphocytic infiltrate, particularly of regulatory T cells, in cancer tissue, is associated with clinical outcome promoting rather than inhibiting cancer development and progression. It has been also verified that the clinical value of lymphocytic infiltration in breast cancers could be subtype-dependent, including the HER2-enriched subtype. In this context, this work summarizes proposed to discuss the prognostic value of regulatory T cell infiltration in microenvironment of HER2-enriched breast cancer.

Objectives: To provide a review of published literature regarding genetic polymorphism of serotonin transporter gene, named as 5-HTTLPR, and its potential role as a susceptibility marker for ethanol abuse in childhood and adolescence., Methods: A literature review of several databases was conducted with the following keywords: 5-HTTLPR, children or adolescents or teenagers, susceptibility, alcohol or ethanol, abuse or misuse., Results: Alcohol interacts with serotonergic synaptic transmission in several ways, and the reduced availability of serotonin transporters might foster brain dysfunction, driving to alcohol abuse. The initial use of ethanol in children and adolescents is determined primarily by environmental influences, whereas the establishment of drinking patterns is strongly controlled by genetic factors. Functional polymorphic variants in the promoter region of the 5-HTTLPR gene have age-dependent effects in alcohol abuse. This polymorphism, mapped to the 5' region of the SLC6A4, is a variable number of tandem repeats (VNTR) and involves a direct repeat of 20-23 base pairs GC-rich sequences, comprising a short (S) allele, consisting of 14 repeats, and a long (L) allele, with 16 repeats. Additional variants have been described, although their influences on childhood and adolescence ethanol use are not clear., Conclusion: The influence of the 5-HTTLPR allelic variants in children and adolescent misuse of alcohol might be considered for clinical management, preventing long-term behavior problem. Identifying genetic markers associated to the potential alcohol misuse or abuse could be useful in guiding management and formulating effective coping strategies.

Background. Celiac disease (CD) is a genetically determined immune-mediated disorder in which gluten immunogenic peptides are presented to CD4 T cells by HLA-DQ2.5, DQ8, DQ2.2, and their combinations. Our aim is to establish a risk gradient for celiac disease based on HLA-DQ profile in a brazilian representative population and the relevance of DQ2.2 in celiac disease development. Materials and Methods. 237 celiac patients and 237 controls (both groups with 164 females and 73 males) were included. All samples were tested for the presence of predisposing HLA-DQ alleles using the PCR-SSP method. Results were considered significant when p < 0.05. Disease risk was expressed as 1 :  N for each HLA-DQ category described at this study. Results. DQ2.5 and/or DQ8 were detected in 224 celiac patients (94.5%) and 84 controls (35.4%). Eight celiac patients (3.4%) and 38 controls (16%) disclosed only DQ2.2. Even though DQ2.2 ( β 2/ β 2 or β 2/x) showed a low CD risk of 1 : 251 and 1 : 550, respectively, the genotype DQ2.5/DQ2.2 ( β 2/ β 2) showed high CD risk of 1 : 10 ( p < 0.0001). The disease risk gradient ranged from 1 : 3014 to 1 : 7. Conclusion. Our study allowed the determination of a risk gradient for celiac disease development in at-risk population, showing that DQ2.2 variant was relevant when associated with DQ2.5., Competing Interests: The authors declare no competing interests regarding the publication of this paper.

Brazil is the only country in the world to propose a universal health care system with the aim of guaranteeing delivery of all levels of health care, free of charge, to a population of over 200 million inhabitants by means of a unified health system ("Sistema Único de Saúde" [SUS]). The national policy of oral health, also known as Smiling Brazil ("Brasil Sorridente"), was implemented in 2004. Oral health was designated as 1 of the 4 priority areas of the SUS, transforming oral health care in Brazil, with the objective that the SUS achieve the integrality of care envisaged at its creation. The aim of this article is to share part of this experience in order to prompt reflection about the inclusion of oral health care in other health care systems around the world. The most significant results of Smiling Brazil can be seen in 3 areas: (1) oral health epidemiological indicators, (2) financial investment and professional development, and (3) the building of an oral health care network throughout the 10 y of the policy. The "Discovery!" article presented here portrays 10 y of evolution; however, it is important to point out that this is a process undergoing construction and that the oral health care network needs to be further expanded, refined, and solidified so that over time and through changes in the political parties in power, Smiling Brazil prevails as a perennial policy and not merely an action by a single government., (© International & American Associations for Dental Research 2015.)

Sheep milk is the third most consumed milk in Brazil. It is much appreciated for its nutritional status and is important for children that have problems with cow milk. Little information is known about the chemical, physical and microbiological composition of sheep milk from South Brazil. Thus, the aim of this study was to describe chemical and microbiological characteristics of sheep milk produced on two rural properties located in southern Brazil (ParanA and Rio Grande do Sul). The chemical composition of sheep milk was 17.32 g/100 g total solids, 5.86 g/100 g total protein, 4.46 g/100 g casein, 1.08 g/100 g whey protein, 7.28 g/100 g fat, 0.93 g/100 g ash, and 3.41 g/100 g lactose. High somatic cell count (1.7x106 cells/mL), total mesophilic bacterias (16.0 x 106 CFU/mL) and psychrotrophics (5.8 x 106 CFU/mL) were observed. Growth of Staphylococcus aureus, enterobacteria and coliforms occurred in 100% of the samples, and 45% of the samples showed growth of Escherichia coli. The sheep milk physical-chemical and microbiology parameters are similar to those presented in the literature for other countries but somatic cell count presented high levels.