Advancements in Biomarkers and Molecular Targets in Hematological Neoplasias.

Hematological neoplasias are among the most common cancers worldwide, and the number of new cases has been on the rise since 1990, reaching 1 [...].

Batimastat Induces Cytotoxic and Cytostatic Effects in In Vitro Models of Hematological Tumors.

The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.

Parthenolide Induces ROS-Mediated Apoptosis in Lymphoid Malignancies.

Lymphoid malignancies are a group of highly heterogeneous diseases frequently associated with constitutive activation of the nuclear factor kappa B (NF-κB) signaling pathway. Parthenolide is a natural compound used to treat migraines and arthritis and found to act as a potent NF-κB signaling inhibitor. This study evaluated in vitro parthenolide efficacy in lymphoid neoplasms. We assessed parthenolide metabolic activity in NCI-H929 (MM), Farage (GCB-DLBCL), Raji (BL), 697 and KOPN-8 (B-ALL), and CEM and MOLT-4 (T-ALL), by resazurin assay. Cell death, cell cycle, mitochondrial membrane potential (ΔΨmit), reactive oxygen species (ROS) and reduced glutathione (GSH) levels, activated caspase-3, FAS-ligand, and phosphorylated NF-κB p65 were evaluated using flow cytometry. CMYC, TP53, GPX1, and TXRND1 expression levels were assessed using qPCR. Our results showed that parthenolide promoted a metabolic activity decrease in all cell lines in a time-, dose-, and cell-line-dependent manner. The mechanism induced by parthenolide was demonstrated to be cell line dependent. Nonetheless, parthenolide promoted cell death by apoptosis with significant ROS increase (peroxides and superoxide anion) and GSH decrease combined with a ΔΨmit reduction across all studied cell lines. Despite the need to further understand parthenolide mechanisms, parthenolide should be considered as a possible new therapeutic approach for B- and T-lymphoid malignancies.

Monocytes in the Characterization of Pain in Palliative Patients with Severe Dementia-A Pilot Study.

In assessing and managing pain, when obtaining a self-report is impossible, therapeutic decision-making becomes more challenging. This study aimed to investigate whether monocytes and some membrane monocyte proteins, identified as a cluster of differentiation (CD), could be potential non-invasive peripheral biomarkers in identifying and characterizing pain in patients with severe dementia. We used 53 blood samples from non-oncological palliative patients, 44 patients with pain (38 of whom had dementia) and 0 without pain or dementia (controls). We evaluated the levels of monocytes and their subtypes, including classic, intermediate, and non-classic, and characterized the levels of specific phenotypic markers, namely CD11c, CD86, CD163, and CD206. We found that the relative concentrations of monocytes, particularly the percentage of classic monocytes, may be a helpful pain biomarker. Furthermore, the CD11c expression levels were significantly higher in patients with mixed pain, while CD163 and CD206 expression levels were significantly higher in patients with nociceptive pain. These findings suggest that the levels of monocytes, particularly the classic subtype, and their phenotype markers CD11c, CD163, and CD206 could serve as pain biomarkers in patients with severe dementia.

AZD-7648, a DNA-PK Inhibitor, Induces DNA Damage, Apoptosis, and Cell Cycle Arrest in Chronic and Acute Myeloid Leukemia Cells.

The non-homologous end joining pathway is vital for repairing DNA double-strand breaks (DSB), with DNA-dependent protein kinase (DNA-PK) playing a critical role. Altered DNA damage response (DDR) in chronic (CML) and acute myeloid leukemia (AML) offers potential therapeutic opportunities. We studied the therapeutic potential of AZD-7648 (DNA-PK inhibitor) in CML and AML cell lines. This study used two CML (K-562 and LAMA-84) and five AML (HEL, HL-60, KG-1, NB-4, and THP-1) cell lines. DDR gene mutations were obtained from the COSMIC database. The copy number and methylation profile were evaluated using MS-MLPA and DDR genes, and telomere length using qPCR. p53 protein expression was assessed using Western Blot, chromosomal damage through cytokinesis-block micronucleus assay, and γH2AX levels and DSB repair kinetics using flow cytometry. Cell density and viability were analyzed using trypan blue assay after treatment with AZD-7648 in concentrations ranging from 10 to 200 µM. Cell death, cell cycle distribution, and cell proliferation rate were assessed using flow cytometry. The cells displayed different DNA baseline damage, DDR gene expressions, mutations, genetic/epigenetic changes, and p53 expression. Only HEL cells displayed inefficient DSB repair. The LAMA-84, HEL, and KG-1 cells were the most sensitive to AZD-7648, whereas HL-60 and K-562 showed a lower effect on density and viability. Besides the reduction in cell proliferation, AZD-7648 induced apoptosis, cell cycle arrest, and DNA damage. In conclusion, these results suggest that AZD-7648 holds promise as a potential therapy for myeloid leukemias, however, with variations in drug sensitivity among tested cell lines, thus supporting further investigation to identify the specific factors influencing sensitivity to this DNA-PK inhibitor.

Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines.

Heat shock protein 90 (HSP90) facilitates folding and stability and prevents the degradation of multiple client proteins. One of these HSP90 clients is BCR-ABL, the oncoprotein characteristic of chronic myeloid leukemia (CML) and the target of tyrosine kinase inhibitors, such as imatinib. Alvespimycin is an HSP90 inhibitor with better pharmacokinetic properties and fewer side effects than other similar drugs, but its role in overcoming imatinib resistance is not yet clarified. This work studied the therapeutic potential of alvespimycin in imatinib-sensitive (K562) and imatinib-resistant (K562-RC and K562-RD) CML cell lines. Metabolic activity was determined by the resazurin assay. Cell death, caspase activity, mitochondrial membrane potential, and cell cycle were evaluated by means of flow cytometry. Cell death was also analyzed by optical microscopy. HSPs expression levels were assessed by western blotting. Alvespimycin reduced metabolic activity in a time-, dose-, and cell line-dependent manner. Resistant cells were more sensitive to alvespimycin with an IC50 of 31 nM for K562-RC and 44 nM for K562-RD, compared to 50 nM for K562. This drug induced apoptosis via the mitochondrial pathway. In K562 cells, alvespimycin induced cell cycle arrest in G0/G1. As a marker of HSP90 inhibition, a significant increase in HSP70 expression was observed. Our results suggest that alvespimycin might be a new therapeutic approach to CML treatment, even in cases of resistance to imatinib.

The virome of the white-winged vampire bat Diaemus youngi is rich in circular DNA viruses.

In the Neotropical region, the white-winged vampire bat (Diaemus youngi) is the rarest of the three species of vampire bats. This bat species feeds preferentially on bird blood, and there is limited information on the viruses infecting D. youngi. Hence, this study aimed to expand the knowledge about the viral diversity associated with D. youngi by sampling and pooling the lungs, liver, kidneys, heart, and intestines of all animals using high-throughput sequencing (HTS) on the Illumina MiSeq platform. A total of three complete and 10 nearly complete circular virus genomes were closely related to gemykrogvirus (Genomoviridae family), smacovirus (Smacoviridae family), and torque teno viruses (TTVs) (Anelloviridae family). In addition, three sequences of bat paramyxovirus were detected and found to be closely related to viruses reported in Pomona roundleaf bats and rodents. The present study provides a snapshot of the viral diversity associated with white-winged vampire bats and provides a baseline for comparison to viruses detected in future outbreaks.

Zinc Prevents DNA Damage in Normal Cells but Shows Genotoxic and Cytotoxic Effects in Acute Myeloid Leukemia Cells.

Genomic instability is prevented by the DNA damage response (DDR). Micronutrients, like zinc (Zn), are cofactors of DDR proteins, and micronutrient deficiencies have been related to increased cancer risk. Acute myeloid leukemia (AML) patients commonly present Zn deficiency. Moreover, reports point to DDR defects in AML. We studied the effects of Zn in DDR modulation in AML. Cell lines of AML (HEL) and normal human lymphocytes (IMC) were cultured in standard culture, Zn depletion, and supplementation (40 µM ZnSO4) conditions and exposed to hydrogen peroxide (H2O2) or ultraviolet (UV) radiation. Chromosomal damage, cell death, and nuclear division indexes (NDI) were assessed through cytokinesis-block micronucleus assay. The phosphorylated histone H2AX (yH2AX) expression was monitored at 0 h, 1 h, and 24 h after exposure. Expression of DDR genes was evaluated by quantitative real time polymerase chain reaction (qPCR). Zn supplementation increased the genotoxicity of H2O2 and UV radiation in AML cells, induced cytotoxic and antiproliferative effects, and led to persistent yH2AX activation. In contrast, in normal lymphocytes, supplementation decreased damage rates, while Zn depletion favored damage accumulation and impaired repair kinetics. Gene expression was not affected by Zn depletion or supplementation. Zn presented a dual role in the modulation of genome damage, preventing damage accumulation in normal cells and increasing genotoxicity and cytotoxicity in AML cells.

Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis.

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants-SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters' SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.

Flow cytometry and targeted immune transcriptomics identify distinct profiles in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors with or without interferon-α.

BACKGROUND: Tumor cells have evolved complex strategies to escape immune surveillance, a process which involves NK cells and T lymphocytes, and various immunological factors. Indeed, tumor cells recruit immunosuppressive cells [including regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSC)] and express factors such as PD-L1. Molecularly targeted therapies, such as imatinib, have off-target effects that may influence immune function. Imatinib has been shown to modulate multiple cell types involved in anti-cancer immune surveillance, with potentially detrimental or favorable outcomes. Imatinib and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) have dramatically changed disease course. Our study aimed to characterize the different populations of the immune system in patients with CML affected by their treatment. METHODS: Forty-one patients with CML [33 treated with TKIs and 8 with TKIs plus interferon (IFN)-α] and 20 controls were enrolled in the present study. Peripheral blood populations of the immune system [referred to as the overview of immune system (OVIS) panel, Treg cells and MDSCs] and PD-1 expression were evaluated by flow cytometry. The immunological profile was assessed using the mRNA Pan-Cancer Immune Profiling Panel and a NanoString nCounter FLEX platform. RESULTS: Patients receiving combination therapy (TKIs + IFN-α) had lower numbers of lymphocytes, particularly T cells [838/µL (95% CI 594-1182)] compared with healthy controls [1500/µL (95% CI 1207 - 1865), p = 0.017]. These patients also had a higher percentage of Treg (9.1%) and CD4+PD-1+ cells (1.65%) compared with controls [Treg (6.1%) and CD4+/PD-1+(0.8%); p ≤ 0.05]. Moreover, patients treated with TKIs had more Mo-MDSCs (12.7%) whereas those treated with TKIs + IFN-α had more Gr-MDSC (21.3%) compared to controls [Mo-MDSC (11.4%) and Gr-MDSC (8.48%); p ≤ 0.05]. CD56bright NK cells, a cell subset endowed with immune-regulatory properties, were increased in patients receiving TKIs plus IFN-α compared with those treated with TKIs alone. Interestingly, serum IL-21 was significantly lower in the TKIs plus IFN-α cohort. Within the group of patients treated with TKI monotherapy, we observed that individuals receiving 2nd generation TKIs had lower percentages of CD4+ Treg (3.63%) and Gr-MDSC (4.2%) compared to patients under imatinib treatment (CD4+ Treg 6.18% and Gr-MDSC 8.2%), but higher levels of PD-1-co-expressing CD4+ cells (1.92%). CONCLUSIONS: Our results suggest that TKIs in combination with IFN-α may promote an enhanced immune suppressive state.

Apoptosis induction and cell cycle arrest of pladienolide B in erythroleukemia cell lines.

Splicing of pre-mRNA into functional mRNA, carried out by the spliceosome, represents a crucial step in eukaryotic gene expression. Mutations and other deregulation in some of the spliceosome components have been identified in multiple pathologies, including hematological malignancies. In this context, we evaluated the therapeutic potential of a splicing inhibitor, Pladienolide B (Pla-B), in two erythroleukemia cell lines. HEL and K562 cell lines were incubated with increasing doses of Pla-B in single and daily administration. Cell viability and density were evaluated using trypan blue assay. Flow cytometry was used to evaluate cell death, cell cycle, and caspase activity. NGS analysis was performed to assess the mutational status of 4 splicing-related genes (SF3B1, U2AF1, ZRSR2 and SRSF2). Expression levels of SF3B1 and unspliced DNAJB1 were evaluated by qPCR. Pla-B significantly decreased the viability and proliferation of both cell lines in time, dose, administration schedule, and cell line-dependent manner. HEL cells were more sensible to Pla-B (IC50 = 1.5 nM) than K562 (IC50 = 25 nM), with an IC50 almost 17 times lower. Pla-B induced cell death, mainly by apoptosis, and cell cycle arrest in G0/G1 phase. No mutations were found in any of the analyzed genes, suggesting that the observed cytotoxic effect is independent of the spliceosome mutations. Splicing modulator Pla-B showed high antitumor activity against HEL and K562 cell lines, inducing apoptosis and cell cycle arrest. These data suggest that Pla-B might represent a new therapeutic approach for erythroleukemia.

Effects of high-oleic peanuts within a hypoenergetic diet on inflammatory and oxidative status of overweight men: a randomised controlled trial.

The consumption of food with MUFA has been associated with improvement of inflammation and oxidative stress in overweight individuals. In the present study, we evaluate the effect of high-oleic peanut intake within a hypoenergetic diet on inflammatory and oxidative status markers in overweight men. Sixty-four overweight men (BMI 26-35 kg/m2, 18-50 years old) participated in this randomised controlled study for 4 weeks, allocated into three groups: control (CT, n 22), conventional peanut (CVP, n 21) and high-oleic peanut (HOP, n 21). They followed a hypoenergetic diet (-250 kcal/d; -1045 kJ/d) with or without 56 g of high-oleic or conventional peanuts. After the intervention, the inflammatory markers did not show significant changes in fasting concentrations or postprandial response among the experimental groups (P > 0·05). The activity of oxidative status markers remained unchanged after the intervention. However, in the CT, malondialdehyde showed lower concentration in comparison with the baseline (P = 0·020) and among the groups (P = 0·002). In the present study, the daily intake of high-oleic peanuts within a hypoenergetic diet did not modify the inflammatory markers and oxidative status in overweight men. More studies are needed to better understand the effect of high-oleic peanut intake on health outcomes.

The fatty acid profile of adipose tissue as a predictor of the ponderal and inflammatory response in adult women six years after bariatric surgery.

BACKGROUND: Adipose tissue is involved in several metabolic changes. This study investigated the association between the fatty acid (FA) composition of subcutaneous (SAT) and visceral (VAT) adipose tissue pre-surgery and the postsurgical response regarding the evolution of weight and concentrations of tumour necrosis factor alpha (TNF) and interleukin 6 (IL-6) in adult women who underwent Roux-en-Y gastric bypass (RYGB, n = 14) or sleeve gastrectomy (SG, n = 19) at one (T1), three (T3) and six (T6) years after surgery. METHODS: Blood samples were collected to obtain plasma for the measurement of IL-6 and TNF. Anthropometric measurements were performed, collecting samples of VAT and SAT during surgery to assess the FA profiles. RESULTS: Weight loss had a positive correlation with the percentage of VAT-C17:0 (T1, T3) and SAT-C18:2 (T1, T3, T6), and it had a negative correlation with SAT-C22:0 (T1, T3) and VAT-C22:0 (T3). Regarding the inflammatory response, SAT-C14:0 (T6), VAT-C14:0 (T6), SAT-C14:1 (baseline), SAT-C15:0 (T6), SAT-C16:1 (T6), VAT-C16:1 (baseline), SAT-C17:1 (T6), VAT-C17:1 (baseline), VAT-C18:1 (T6), and VAT-C20:1 (T6) exhibited positive correlations with the concentration of IL-6, which were different from the correlations of IL-6 concentrations with SAT-C18:2, VAT-C18:2 (T6), and VAT-C18:3 (T6). The FA SAT-C18:0 (T1) was negatively correlated with TNF concentrations. CONCLUSIONS: Saturated FAs were predominantly proinflammatory, primarily in the late postoperative period. Alternately, the polyunsaturated FAs exhibited anti-inflammatory potential and predicted weight loss. Thus, the FA profile of the adipose tissue of obese adult women may be a predictor of the ponderal and inflammatory response 6 years after bariatric surgery. TRIAL REGISTRATION: This study was approved by the ethics committee of Federal University of Viçosa; Registration n. 17287913.2.0000.5153; Date: 07/05/2013.

Paracrine effect of carbon monoxide - astrocytes promote neuroprotection through purinergic signaling in mice.

The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not with CO. The CO-pre-treated astrocytes reduced neuronal cell death, and the cellular mechanisms were investigated, focusing on purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture medium. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection through astrocytes. Likewise, knocking down expression of the neuronal P1 adenosine receptor A2A-R (encoded by Adora2a) reverted the neuroprotective effects of CO-exposed astrocytes. The neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolism into adenosine. Finally, the neuronal downstream event involves TrkB (also known as NTRK2) receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptors reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio of BDNF to pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism through purinergic signaling.

Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) share common features: elevated oxidative stress, DNA repair deficiency, and aberrant DNA methylation. We performed a hospital-based case-control study to evaluate the association in variants of genes involved in oxidative stress, folate metabolism, DNA repair, and DNA methylation with susceptibility and prognosis of these malignancies. To that end, 16 SNPs (one per gene: CAT, CYBA, DNMT1, DNMT3A, DNMT3B, GPX1, KEAP1, MPO, MTRR, NEIL1, NFE2F2, OGG1, SLC19A1, SOD1, SOD2, and XRCC1) were genotyped in 191 patients (101 MDS and 90 AML) and 261 controls. We also measured oxidative stress (reactive oxygen species/total antioxidant status ratio), DNA damage (8-hydroxy-2'-deoxyguanosine), and DNA methylation (5-methylcytosine) in 50 subjects (40 MDS and 10 controls). Results showed that five genes (GPX1, NEIL1, NFE2L2, OGG1, and SOD2) were associated with MDS, two (DNMT3B and SLC19A1) with AML, and two (CYBA and DNMT1) with both diseases. We observed a correlation of CYBA TT, GPX1 TT, and SOD2 CC genotypes with increased oxidative stress levels, as well as NEIL1 TT and OGG1 GG genotypes with higher DNA damage. The 5-methylcytosine levels were negatively associated with DNMT1 CC, DNMT3A CC, and MTRR AA genotypes, and positively with DNMT3B CC genotype. Furthermore, DNMT3A, MTRR, NEIL1, and OGG1 variants modulated AML transformation in MDS patients. Additionally, DNMT3A, OGG1, GPX1, and KEAP1 variants influenced survival of MDS and AML patients. Altogether, data suggest that genetic variability influence predisposition and prognosis of MDS and AML patients, as well AML transformation rate in MDS patients. © 2016 Wiley Periodicals, Inc.

Higher plasma lipopolysaccharide concentrations are associated with less favorable phenotype in overweight/obese men.

PURPOSE: Lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria might be an inflammation trigger in adipose tissue. It has recently been proposed that there is a link between adipose tissue distribution and blood LPS. However, the number of studies on this topic is scarce, and further investigation in humans is required. In this study, we explored the association between plasma LPS concentrations and body fat distribution, as well as the biochemical parameters that may indicate the presence of metabolic disorders. METHODS: Sixty-seven young adult men with body mass index of 26-35 kg/m(2) were evaluated. Anthropometry, body composition and body fat distribution, blood pressure, energy expenditure, physical activity level, dietary intake, and biochemical parameters were assessed. RESULTS: Men with median plasma LPS ≥ 0.9 EU/mL presented higher sagittal abdominal diameter, trunk fat percentage, and android fat percentage, and mass, insulin and alanine aminotransferase concentrations, homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell dysfunction (HOMA-B) than those with lower plasma LPS. LPS correlated positively with the trunk fat percentage, and android fat percentage, and mass, insulin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase concentrations, as well as HOMA-IR and HOMA-B. CONCLUSION: Our results suggest that a higher plasma LPS concentration is associated with a less favorable phenotype as characterized by higher central adiposity, higher values of HOMA-IR, and beta cell function impairment in overweight/obese men.

Eating carbohydrate mostly at lunch and protein mostly at dinner within a covert hypocaloric diet influences morning glucose homeostasis in overweight/obese men.

PURPOSE: To evaluate the effects of two dietary patterns in which carbohydrates and proteins were eaten mostly at lunch or dinner on body weight and composition, energy metabolism, and biochemical markers in overweight/obese men. METHODS: Fifty-eight men (30.0 ± 7.4 years; 30.8 ± 2.4 kg/m(2)) followed a covert hypocaloric balanced diet (-10 % of daily energy requirements) during 8 weeks. Subjects were randomly assigned to three groups: control diet (CT); diurnal carbohydrate/nocturnal protein (DCNP); and nocturnal carbohydrate/diurnal protein (NCDP). Main analyzed outcomes were weight loss, body composition, diet-induced thermogenesis (DIT), and glucose/lipid profile. RESULTS: In all groups, a significant decrease in body weight, BMI, and fat mass (kg and %) was verified, without differences between groups. Interestingly, within group analyses showed that the fat-free mass (kg) significantly decreased in NCDP and in CT after 8-week intervention, but not in DCNP. A detrimental increase in fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMAIR) was verified only in DCNP, while NCDP and CT groups presented a non-significant reduction. Moreover, significant differences between DCNP and the other groups were detected for fasting insulin and HOMAIR. After the adjustments, NCDP presented a significantly higher DIT and energy expenditure after lunch, compared with DCNP, but after dinner, there were no differences among groups. CONCLUSION: Eating carbohydrates mostly at dinner and protein mostly at lunch within a hypocaloric balanced diet had similar effect on body composition and biochemical markers, but higher effect on DIT compared with control diet. Moreover, eating carbohydrates mostly at lunch and protein mostly at dinner had a deleterious impact on glucose homeostasis.

Nursing care for hospitalized older adults - fall accidents versus safe mobility: a scoping review.

OBJECTIVES: to map the constituent elements of the safe mobility concept present in hospital care for older adults. METHODS: a scoping review of 35 articles searched in databases and gray literature - BDENF/VHL, Scopus, CINAHL/EBSCO, Embase, Web of Science, PEDro, MEDLINE/PubMed and CAPES Theses and Dissertations Catalog. No time or language cut-off was established. RESULTS: none of the studies presented a clear safe mobility concept, however its constituent elements involve factors related to patient (behavioral factors, conditions, diseases, signs and symptoms, nutritional status, age, balance, strength, gait quality, sleep), the institution (environment, treatment devices, guidelines, medications and polypharmacy, material and human resources and clothing/shoes) and the nature of the interventions (related to the patient, institution and family). FINAL CONSIDERATIONS: the constituent elements of safe mobility express hospital units' capacity to guarantee care and protection from fall accidents for hospitalized older adults.

Steroidal epoxides as anticancer agents in lung, prostate and breast cancers: The case of 1,2-epoxysteroids.

Cancer continues to be a serious threat to human health worldwide. Lung, prostate and triple-negative breast cancers are amongst the most incident and deadliest cancers. Steroidal compounds are one of the most diversified therapeutic classes of compounds and they were proven to be efficient against several types of cancer. The epoxide function has been frequently associated with anticancer activity, particularly the 1,2-epoxide function. For this reason, three 1,2-epoxysteroid derivatives previously synthesised (EP1, EP2 and EP3) and one synthesised for the first time (oxysteride) were evaluated against H1299 (lung), PC3 (prostate) and HCC1806 (triple-negative breast) cancer cell lines. A human non-tumour cell line, MRC-5 (normal lung cell line) was also used. EP2 was the most active compound in all cell lines with IC50 values of 2.50, 3.67 and 1.95 µM, followed by EP3 with IC50 values of 12.65, 15.10 and 14.16 µM in H1299, PC3 and HCC1806 cells, respectively. Additional studies demonstrated that EP2 and EP3 induced cell death by apoptosis at lower doses and apoptosis/necrosis at higher doses, proving that their effects were dose-dependent. Both compounds also exerted their cytotoxicity by ROS production and by inducing double-strand breaks. Furthermore, EP2 and EP3 proved to be much less toxic against a normal lung cell line, MRC5, indicating that both compounds might be selective, and they also demonstrated suitable in silico ADME and toxicity parameters. Finally, none of the compounds induced haemoglobin release. Altogether, these results point out the extreme relevance of both compounds, especially EP2, in the potential treatment of these types of cancer.

An outbreak of type C botulism in free-ranging Southern lapwing (Vanellus chilensis).

In the fall of 2021, a significant mortality event in free-ranging Southern Lapwing (Vanellus chilensis) occurred on a soccer field in southern Brazil. Approximately 130 adult southern lapwings died after showing weakness and flaccid paralysis, characterized by the inability to move or fly and drooped wings. Due to the large number of animals affected, there was concern that they had been criminally poisoned. The affected birds were found to have ingested maggots in fresh poultry litter incorporated into the grass surface. Postmortem examinations of four southern lapwings revealed no significant gross and histological findings. Polymerase Chain Reaction (PCR) for influenza A virus, flavivirus, and paramyxovirus was negative. Based on the epidemiological and clinical findings and the negative viral results, a presumptive diagnosis of botulism was made. This diagnosis was confirmed through mouse bioassay and seroneutralization, which detected botulinum toxin type C. Maggots loaded with botulinum neurotoxins were the probable vehicle for intoxication in the outbreak. Considering the impact of avian botulism on wild bird populations, our results may help prevent similar outbreaks in the future.