Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and ...chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.
Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this ...can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.
Zidovudine (AZT) is one of first choice drugs for the treatment of acquired immunodeficiency syndrome (AIDS). Despite its efficacy to control virus replication, the extent of adverse effects and the ...therapeutic regimen are directly related to patients’ non-compliance. In this work, we evaluated the permeability and in vivo distribution of AZT incorporated into poly(Ɛ-caprolactone), PCL, nanoparticles (AZT-NP) aiming to reduce the normally observed side effects and increase the drug bioavailability. AZT-NP were obtained by interfacial deposition of preformed polymer. The mean diameter of the nanoparticles was 283.4 nm ± 17.0 with a polydispersity index of 0.232 ± 0.073. The nanoparticles presented a zeta potential of − 32.4 mV ± 3.3, entrapment rate of 53.11% ± 9.25, and were stable for at least 7 days. The drug and the polymer showed no incompatibility in thermal analysis. The permeability of AZT across Caco-2 cells was 22-fold higher for AZT-NP compared to the drug solution. The nanoparticles were able to release AZT in vivo after oral administration in mice, and the plasma levels of labeled AZT-NP were higher and more constant when compared to free labeled AZT. Thus, AZT-NP demonstrated superior performance compared to the drug solution in vivo and in vitro, showing the potential of this system for the treatment of AIDS.
•TSM-pathogenic strains of B. bassiana were not selective against adults of three Neoseiulus species.•Neoseiulus barkeri was less susceptible to fungal infections than N. californicus and N. ...idaeus.•Very low RH conditions negatively affect the biology and activity of Neoseiulus spp.•The predatory mites N. californicus and N. idaeus were more tolerant to drought conditions.
Predatory mites and invertebrate-pathogenic fungi have been used as biological control agents in a complementary way to suppress two-spotted spider mite (TSM) populations, which are a key pest of horticultural crops worldwide. However, their performance can be lowered by both biotic (e.g., intraguild interactions) and abiotic stress (especially relative humidity - RH). The present study evaluated the susceptibility of three predatory phytoseiid mite species in the genus Neoseiulus – N. californicus, N. idaeus, and N. barkeri – to infection by selected spider mite-pathogenic Beauveria bassiana strains as well as their predation capacity and resilience under simulated drought conditions. The two selected B. bassiana strains induced TSM mortality above 70 %. All three Neoseiulus mite species also showed susceptibility to both strains; however, N. barkeri was less susceptible to fungal infections than the other Neoseiulus species (with mortality < 65 % and without reduction of oviposition). All three Neoseiulus species were negatively affected by low RH conditions. Neoseiulus barkeri was the most affected with a drastic reduction in TSM egg consumption (about 40 %) and preventing the deposition of eggs by females. The egg consumption by N. californicus and N. idaeus was not affected by low RH conditions; however, both predatory mites reduced the number of eggs laid per female. Thus, the efficiency of the conversion of food into egg biomass for all three Neoseiulus species decreased under low RH conditions, dropping to zero for N. barkeri. We showed that the simultaneous use of B. bassiana and Neoseiulus had a detrimental effect on predatory mite survival and progeny, indicating the need for further development of new strategies which combine these biological control agents.
The main hallmarks of cancer include sustaining proliferative signaling and resisting cell death. We analyzed the genes of the WNT pathway and seven cross-linked pathways that may explain the ...differences in aggressiveness among cancer types. We divided six cancer types (liver, lung, stomach, kidney, prostate, and thyroid) into classes of high (H) and low (L) aggressiveness considering the TCGA data, and their correlations between Shannon entropy and 5-year overall survival (OS). Then, we used principal component analysis (PCA), a random forest classifier (RFC), and protein-protein interactions (PPI) to find the genes that correlated with aggressiveness. Using PCA, we found
,
,
,
,
,
,
,
, and
. Except for
, the RFC analysis showed a different list, which was
,
,
,
,
,
,
,
,
, and
. Both methods use different algorithmic approaches and have different purposes, which explains the discrepancy between the two gene lists. The key genes of aggressiveness found by PCA were those that maximized the separation of H and L classes according to its third component, which represented 19% of the total variance. By contrast, RFC classified whether the RNA-seq of a tumor sample was of the H or L type. Interestingly, PPIs showed that the genes of PCA and RFC lists were connected neighbors in the PPI signaling network of WNT and cross-linked pathways.
Introduction. Clinical complications in sickle cell anemia (SCA) are heterogeneous and involve several molecules. It has been suggested that SCA individuals present a dyslipidemic phenotype and that ...lipid parameters are associated with severe clinical complications, such as pulmonary hypertension. We sought to investigate associations between lipid parameters and clinical manifestations, as well as other laboratory parameters in a population of pediatric SCA patients. Methods. Our cross-sectional evaluation included 126 SCA patients in steady state and who were not undergoing lipid-lowering therapy. Hematological and biochemical parameters were characterized, and previous clinical manifestations were investigated. Results. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels were increased in patients with a previous history of pneumonia, which also positively correlated with HbS levels. Decreased LDL-C levels were also associated with leg ulcers and anemia. Elevated high-density lipoprotein cholesterol (HDL-C) levels were associated with pain crises, increased viscosity, and decreased hemolysis. Several studies have determined that lipids play a role in the vascular impairment seen in SCA, which was corroborated by our findings. Conclusions. In sum, our results suggest that total cholesterol, HDL-C, and LDL-C levels are associated with hemolysis and anemia markers and, most importantly, with clinical complications related to vasculopathy in SCA.
Introduction
The clarification of etiopathology, the improvement of chemotherapy regimens and their risk stratifications, and the improvement in treatment support have increased the survival of ...children and adolescents affected by Acute Lymphoblastic Leukemia (ALL) past few years. This study aimed to estimate overall survival (OS) and event-free survival (EFS) in an onco-hematology treatment center in Brazil, reports the main clinical-laboratory characteristics of patients at diagnosis, verify the frequency of treatment-related adverse effects and the main causes of death.
Material and methods
Retrospective analysis involving patients diagnosed with ALL, treated with the protocol of the Brazilian Group for Treatment of Leukemias in Childhood (GBTLI), between 2010 and 2020 was carried out; the outcomes (relapse, deaths, development of new neoplasms) were analyzed SPSS® software was used for the statistical analyses, and the
p
-value was considered significant when less than 0.05 for all analyses.
Results
109 patients were included in the study; the median age was 5 years, with a slight predominance of males. Sixty-six patients were classified as high-risk (HR) group and 43 patients were classified as low-risk (LR) group. After 5 years of diagnosis, the OS was 71.5%, and the EFS was 65%. No statistical difference was found between the HR and LR groups for OS and EFS, while leukocyte counts were statistically associated with the outcome of death (
p
= 0.028). Among the patients, 28 (25.6%) died due to infection accounting 46.4% of death causes. Among the 34 patients with unfavorable outcomes (death and/or relapse), 32 had no research for the minimal residual disease at the end of remission induction, and 25 were not investigated for the presence of chromosomal abnormalities. The most reported complications and treatment-related adverse effects were increased liver transaminases (85.9%), airway infection (79.4%), oral mucositis (67.2%), febrile neutropenia (64.4%), and diarrhea (36.4%).
Conclusions
The rates of OS and EFS obtained in this cohort are similar to those obtained in the few previous similar studies in Brazil and lower than those carried out in developed countries. The unavailability of prognostic tests may have hindered risk stratification and influenced the results obtained.
Individuals with sickle cell anemia (SCA) present chronic anemia, hemolysis, an exacerbated inflammatory response, and heterogeneous clinical complications, which may be modulated by the transforming ...growth factor beta (TGF-β) pathway. Thus, we aimed to investigate polymorphisms (rs1805110 and rs7526590) of the transforming growth factor beta receptor III gene (TGFBR3) with regard to laboratory biomarkers and clinical manifestations in individuals with SCA. Hematological, biochemical, immunological, and genetic analyses were carried out, as well as serum endothelin-1 measurements. The minor allele (A) of the TGFBR3 rs1805110 polymorphism was associated with increased hemoglobin, hematocrit, reticulocyte counts, total cholesterol, low-density lipoprotein, uric acid, and endothelin levels, as well as decreased platelet distribution width (PDW) and the occurrence of bone alterations. The minor allele (T) of TGFBR3 rs7526590 was associated with increased red cell distribution width, PDW, alkaline phosphatase, aspartate aminotransferase, total and indirect bilirubin, and lactate dehydrogenase levels, as well as lower ferritin levels and the occurrence of leg ulcers. Our data suggest that the minor allele (A) of TGFBR3 rs1805110 is associated with inflammation and bone alterations, while the minor allele (T) of TGFBR3 rs7526590 is related to hemolysis and the occurrence of leg ulcers.
Sickle cell anemia (SCA) patients exhibit sub-phenotypes associated to hemolysis and vaso-occlusion. The disease has a chronic inflammatory nature that has been also associated to alterations in the ...lipid profile. This study aims to analyze hematological and biochemical parameters to provide knowledge about the SCA sub-phenotypes previously described and suggest a dyslipidemic sub-phenotype.
A cross-sectional study was conducted from 2013 to 2014, and 99 SCA patients in steady state were enrolled. We assessed correlations and associations with hematological and biochemical data and investigated the co-inheritance of -α
-thalassemia (-α
-thal). Correlation analyses were performed using Spearman and Pearson coefficient. The median of quantitative variables between two groups was compared using t-test and Mann-Whitney. P-values <0.05 were considered statistically significant.
We found significant association of high lactate dehydrogenase levels with decreased red blood cell count and hematocrit as well as high levels of total and indirect bilirubin. SCA patients with low nitric oxide metabolites had high total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol and reduced very low-density cholesterol, triglycerides, direct bilirubin level and reticulocyte counts. In SCA patients with high-density lipoprotein cholesterol greater than 40 mg/dL, we observed increased red blood cell count, hemoglobin, hematocrit, and fetal hemoglobin and decreased nitric oxide metabolites levels. The presence of -α
-thal was associated with high red blood cell count and low mean corpuscular volume, mean corpuscular hemoglobin, platelet count and total and indirect bilirubin levels.
Our results provide additional information about the association between biomarkers and co-inheritance of -α
-thal in SCA, and suggest the role of dyslipidemia and nitric oxide metabolites in the characterization of this sub-phenotype.
PDF
