Integrated genetic, epigenetic, and immune landscape of TP53 mutant AML and higher risk MDS treated with azacitidine.

Background: TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53-mutated AML/HR-MDS is not well defined. Objectives: To define the genetic, epigenetic, and immunologic landscape of TP53-mutant and TP53 wild-type AML and HR-MDS patients. Design: Post hoc analysis of TP53-mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab. Methods: We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53-mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial. Results: Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53-mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53-mutant samples suggesting a novel therapeutic target. Conclusion: This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53-mutant AML/HR-MDS with mono- or multihit TP53 mutation status. Trial registration: FUSION trial (NCT02775903).

Effect of quantitative feed restriction and sex class on sheep skin quality.

The aim was to evaluate the quality of the sheep skin of different sex classes submitted to different levels of feed restriction. Sheep without defined racial pattern of different sex classes (15 non-castrated males, 15 castrated males and 15 females), with initial body weight of 18.1 ± 0.4 kg and mean age of 90 days were distributed in a factorial 3 × 3, with three sex classes and 3 levels of feed restriction (ad libitum intake and restricted intake at 70 and 80%), with 5 repetitions. After slaughter, the skins were collected for physical-mechanical tests. The effect of the sex classes x levels of dietary restriction interaction was observed for transverse thickness and longitudinal rupture elongation (p < 0.05). Animals fed ad libitum had greater longitudinal transverse thickness (p < 0.05). Animals fed ad libitum and 70% feed restriction showed greater transverse elongation at break (p < 0.05). As for the difference between sex classes in the transverse thickness variable for tearing strength, the interaction sex classes x levels of feed restriction for transverse thickness, longitudinal thickness, transverse tearing strength and longitudinal tearing strength occurred (p < 0.05). Feed restriction reduces the physical quality of the skin of sheep of different sex classes, and the use of castrated male sheep in positive energy balance is recommended to obtain leather with greater thickness, longitudinal rupture elongation and transverse tear strength.

Interaction between residual feed intake and thermal environment on performance, nitrogen balance, ingestive behavior and carcass yield of dorper lambs.

Residual feed intake (RFI) is a nutritional variable used in genetic improvement programs, the relationship between the environment and the availability of energy and protein in the diet has not yet been explored. Thus, the aim was to evaluate interactions between RFI and thermal environment on performance, nitrogen balance, ingestive behavior and carcass yield of Dorper lambs receiving diets containing different concentrate levels. Dorper lambs (male, n = 64, 17.83 ± 2.43 kg and 110 ± 10 days of age) were confined individually for 40 days for RFI classification. Lambs were separated into positive RFI (n = 30) and negative RFI (n = 30) and remained confined for another 60 days. The animals were distributed in a randomized block design, with a 2 × 2 × 3 factorial scheme, with 2 confinement environments (full sun or shade), 2 groups of feed efficiency (RFI positive or RFI negative) and three diets containing different concentrate levels (30, 45 and 60%), with 5 replications in each treatment. Isolated effects of concentrate level were observed for dry matter intake and digestibility, feeding, rumination, idle and chewing times, feeding efficiency, ingested, excreted and absorbed nitrogen, and on cooling losses, hot and cold carcass yield (P < 0.05). There was an effect of environment × concentrate interaction on performance, retained nitrogen and nitrogen balance (P < 0.05). There was an effect of RFI × environment interaction on the dry matter rumination efficiency, hot and cold carcass weight (P < 0.05). Under experimental conditions, RFI did not influence the productive performance of Dorper lambs. Interactions between environment and diet indicate better performance for Dorper lamb confined in the shade and receiving a higher proportion of concentrate. Animals with negative RFI show better performance and carcass weight when confined in shade, while animals with positive RFI showed better responses to these variables when confined in full sun.

Changes in the physiological, hematological and parasitological parameters of Dorper sheep in relation to residual feed intake and confinement environment.

The selection of animals with greater feed efficiency has unknown parasitological and physiological parameters when confined in full sun or shade. Thus, we aimed to assess the effect of residual feed intake (RFI) and the confinement environment on the hematological, parasitological and physiological parameters in male Dorper sheep (n = 60; 30 with positive RFI and 30 with negative RFI) distributed in 2 confinement environments (full sun and shade), in a 2 × 2 factorial scheme, with 15 animals for treatment. Animals kept in the shade showed an increase (P < 0.05) of erythrocytes, hemoglobin and albumin. Animals kept in full sun showed higherOocysts gamma glutamyltransferase, direct bilirubin, transaminase aspartate and respiratory rate (P<0.05). There was a higher incidence of Eimeria spp oocysts in RFI negative animals (P<0.05). Positive RFI animals increased respiratory rate (P<0.05). The RFI did not influence the blood parameters of Dorper sheep, however, it had an effect on respiratory rate and presence of Eimeria spp. oocysts. Thermal environment promoted changes in blood parameters and the physiological parameters of Dorper sheep.

Survival outcomes in patients with acute myeloid leukaemia who received subsequent therapy for relapse in QUAZAR AML-001.

In the phase 3 QUAZAR AML-001 trial (NCT01757535) of patients with acute myeloid leukaemia (AML) in remission following intensive chemotherapy (IC) and ineligible for haematopoietic stem cell transplant (HSCT), oral azacitidine (Oral-AZA) maintenance significantly prolonged overall survival (OS) versus placebo. The impact of subsequent treatment following maintenance has not been evaluated. In this post hoc analysis, OS was estimated for patients who received subsequent AML therapy, and by regimen received (IC or lower-intensity therapy). First subsequent therapy (FST) was administered after treatment discontinuation in 134/238 Oral-AZA and 173/234 placebo patients. OS from randomization in patients who received FST after Oral-AZA versus placebo was 17.8 versus 12.9 months (HR: 0.82 [95% CI: 0.64-1.04], median follow-up: 56.7 months); OS from FST was similar between arms. Among patients who received injectable hypomethylating agents as FST, median OS was 8.2 versus 4.9 months in the Oral-AZA versus placebo groups (HR: 0.66 [95% CI: 0.41-1.06]). Forty-eight patients (16/238 Oral-AZA, 32/234 placebo) received HSCT following treatment discontinuation, including six Oral-AZA patients still in first remission; Oral-AZA OS benefit persisted when censoring these patients. Oral-AZA maintenance can prolong AML remission duration without negatively impacting survival outcomes after salvage therapies.

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase.

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.

Non-invasive methods to quantify the carcass parameters of sheep: Interaction between thermal environment and residual feed intake.

The thermal environment is important in unit production because the perception of thermal stress can reduce fertility, and productive performance, therefore its management is necessary. The use of non-invasive methods, such as infrared thermography and real-time ultrasonography, are widely used to evaluate indicators in animal production, without the need to slaughter the animals. Thus, we aimed to assess the effect of the thermal environment on the physiological parameters and carcass characteristics of Dorper sheep with positive and negative residual feed intake (RFI) using infrared thermography and real-time ultrasonography techniques. Twenty uncastrated male Dorper sheep (17.8 ± 2.4 kg) were confined for 40 days for RFI classification. Sheep were separated into positive RFI (n = 10) and negative RFI (n = 10). The experimental design was in randomized blocks, in a 2 × 2 factorial arrangement, with 2 thermal environments (full sun or shade) and two feed efficiency groups (positive RFI or negative RFI), with 5 replications. The sheep remained in confinement for 60 days. The animals were slaughtered at the end of the experiment and the carcasses dissected for tissue separation. Rectal temperature (RT) and respiratory rate (RR) were measured at two times (14:00 h and 18:00 h) for periods of 5 days. The RR was determined by indirect auscultation of heart sounds at the level of the laryngotracheal region. The RT was measured introduced a digital clinical thermometer into the animal's rectum. Surface temperature (ST) was obtained using a thermographic infrared camera, collecting the temperatures of the eyeball and skin surface in the regions of the head, ribs, rump, flank and shin. Sheep confined in full sun showed higher RR (P = 0.0001), ST ribs (P = 0.0020), ST rumb (P = 0.0055), ST flank (P = 0.0001) and heat tolerance coefficient (HTC) (P = 0.0010). For sheep confined in full sun, a strong correlation was observed between the RR and the mean ST (MST; r = 0.6826; P = 0.0236) and between the final loin eye area (LEAf) with the real LEA (LEAr) (r = 0.9263; P = 0.0001) and slaughter body weight (SBW) (r = 0.7532; P = 0.0325). For negative RFI sheep, a positive correlation was observed between the RR and the ST rump (r = 0.7343; P = 0.0025) and ST ribs (r = 0.6560; P = 0.0178) and the MST (r = 0.7435; P = 0.0001), between the MST and the LEAr (r = 0.6837; P = 0.0025) and the final LEA (r = 0.6771; P = 0.0144), and between the final LEA and LEAr (r = 0.9942; P = 0.0001), BW (r = 0.8415; P = 0.0277) and MST (r = 0.6771; P = 0.0045). Positive RFI sheep confined to shade showed a high correlation between final LEA and LEAr (r = 0.9372; P = 0.0001). The use of shading in confined Dorper sheep, regardless of the RFI classification, reduces the effects of heat stress on physiological parameters.

Evaluation of the Hematological Patterns from Up to 985 Days of Long COVID: A Cross-Sectional Study.

Long COVID affects many individuals following acute coronavirus disease 2019 (COVID-19), and hematological changes can persist after the acute COVID-19 phase. This study aimed to evaluate these hematological laboratory markers, linking them to clinical findings and long-term outcomes in patients with long COVID. This cross-sectional study selected participants from a 'long COVID' clinical care program in the Amazon region. Clinical data and baseline demographics were obtained, and blood samples were collected to quantify erythrogram-, leukogram-, and plateletgram-related markers. Long COVID was reported for up to 985 days. Patients hospitalized in the acute phase had higher mean red/white blood cell, platelet, and plateletcrit levels and red blood cell distribution width. Furthermore, hematimetric parameters were higher in shorter periods of long COVID than in longer periods. Patients with more than six concomitant long COVID symptoms had a higher white blood cell count, a shorter prothrombin time (PT), and increased PT activity. Our results indicate there may be a compensatory mechanism for erythrogram-related markers within 985 days of long COVID. Increased levels of leukogram-related markers and coagulation activity were observed in the worst long COVID groups, indicating an exacerbated response after the acute disturbance, which is uncertain and requires further investigation.

Liver Function in Patients with Long-Term Coronavirus Disease 2019 of up to 20 Months: A Cross-Sectional Study.

The long-term laboratory aspects of the effects of coronavirus disease 2019 (COVID-19) on liver function are still not well understood. Therefore, this study aimed to evaluate the hepatic clinical laboratory profile of patients with up to 20 months of long-term COVID-19. A total of 243 patients of both sexes aged 18 years or older admitted during the acute phase of COVID-19 were included in this study. Liver function analysis was performed. Changes were identified in the mean levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), and ferritin. A ferritin level of >300 U/L was observed in the group that presented more changes in liver function markers (ALT, AST, and GGT). Age ≥ 60 years, male sex, AST level > 25 U/L, and GGT level ≥ 50 or 32 U/L were associated with an ALT level > 29 U/L. A correlation was found between ALT and AST, LDH, GGT, and ferritin. Our findings suggest that ALT and AST levels may be elevated in patients with long-term COVID-19, especially in those hospitalised during the acute phase. In addition, an ALT level > 29 U/L was associated with changes in the levels of other markers of liver injury, such as LDH, GGT, and ferritin.

Metabolic Profile of Patients with Long COVID: A Cross-Sectional Study.

A significant proportion of patients experience a wide range of symptoms following acute coronavirus disease 2019 (COVID-19). Laboratory analyses of long COVID have demonstrated imbalances in metabolic parameters, suggesting that it is one of the many outcomes induced by long COVID. Therefore, this study aimed to illustrate the clinical and laboratory markers related to the course of the disease in patients with long COVID. Participants were selected using a clinical care programme for long COVID in the Amazon region. Clinical and sociodemographic data and glycaemic, lipid, and inflammatory screening markers were collected, and cross-sectionally analysed between the long COVID-19 outcome groups. Of the 215 participants, most were female and not elderly, and 78 were hospitalised during the acute COVID-19 phase. The main long COVID symptoms reported were fatigue, dyspnoea, and muscle weakness. Our main findings show that abnormal metabolic profiles (such as high body mass index measurement and high triglyceride, glycated haemoglobin A1c, and ferritin levels) are more prevalent in worse long COVID presentations (such as previous hospitalisation and more long-term symptoms). This prevalence may suggest a propensity for patients with long COVID to present abnormalities in the markers involved in cardiometabolic health.

Oral azacitidine modulates the bone marrow microenvironment in patients with acute myeloid leukaemia in remission: A subanalysis from the QUAZAR AML-001 trial.

Oral azacitidine (Oral-AZA) maintenance therapy improved relapse-free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML-001 study. Immune profiling was performed on the bone marrow (BM) at remission and on-treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on-treatment immune effects by Oral-AZA with clinical outcomes. Post-IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T-cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD-L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD-L2+. High co-expression of T-cell exhaustion markers PD-1 and TIM-3 was associated with inferior outcomes. Oral-AZA augmented T-cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T-cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T-cell content and expression of T-cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral-AZA modulates T-cell activity in the maintenance setting of AML, and these immune-mediated responses are associated with clinical outcomes.

Accuracy Study of Kato-Katz and Helmintex Methods for Diagnosis of Schistosomiasis Mansoni in a Moderate Endemicity Area in Sergipe, Northeastern Brazil.

Schistosomiasis is a neglected tropical disease (NTD) caused by blood flukes from the genus Schistosoma. Brazil hosts the main endemic area in the Americas, where Schistosoma mansoni is the only species causing the disease. Kato-Katz (KK) thick smear is the WHO recommended screening test for populational studies, but there is growing evidence for the sensitivity limitations associated with KK, especially in areas with low parasite loads. Helmintex (HTX) is another highly sensitive egg-detection method, based on the magnetic properties of S. mansoni eggs and their isolation in a magnetic field. The objective of this study is to evaluate both KK and HTX in a moderate endemic locality, Areia Branca, located in the municipality of Pacatuba, in the state of Sergipe in northeastern Brazil. From 234 individual fecal samples, two KK thick smears were prepared and evaluated for each sample. Similarly, 30 g of each fecal sample was processed by HTX protocol. Eggs were detected in 80 (34.18%) residents. Twenty-three (9.83%) samples were positive for eggs (only by KK), and 77 (32.91%) samples showed positive for eggs (only by HTX). Sensitivity, specificity, and accuracy estimates gave values of 28.75%, 100% and 75.64%, respectively, for KK, and 96.25%, 100% and 98.72% respectively, for HTX. The positive predictive value was 100% for both methods, while the negative predictive value was 72.99% for KK and 98.09% for HTX. Overall, HTX presented a superior performance compared to the one sample, two slides KK examination. The study confirms the role of HTX as a reference method for the definition of true-positive samples in comparative accuracy studies and its potential role in the late stages when the certification of schistosomiasis transmission interruption is required. Diagnostic tests are important tools for the elimination of this NTD, besides the effective implementation of safe water, basic sanitation, snail control, and the treatment of infected populations.

Condensed tannins to increase bioactive fatty acids in the milk from Canindé, Repartida, and Saanen goats.

Bioactive fatty acids present in goat milk have the ability to reduce the risks of coronary heart disease in humans, and condensed tannins (CT) can modulate the polyunsaturated fatty acids (PUFA) biohydrogenation process in the rumen and consequently increase the levels of these fatty acids. Thus, the objective was to evaluate the inclusion of CT in the diet for Canindé, Repartida, and Saanen goats to increase the level of bioactive fatty acids in milk. Twenty-two lactating does of three genetic groups, six Canindé, eight Repartida, and eight Saanen, were randomly assigned in a 3 × 2 factorial arrangement of three genetic groups and two diets (control and with 50 g CT/kg DM). The inclusion of CT in the diet did not change (P > 0.05) nutrient intake and performance. However, the inclusion of CT promoted an increase (P < 0.05) in C14:1; cis-9; C18:2n6; C18:3n6; C18:3n3; PUFA; and long-chain fatty acids and reduction (P < 0.05) of C11; C12; C14; ω6/ω3; and atherogenicity index in milk fat. Thus, it is recommended to include CT in the diet for Canindé, Repartida, and Saanen goats to increase the level of bioactive fatty acids in milk. The inclusion of the tannins of Acacia mearnsii promoted an increase in C14:1; cis-9; C18:2n6; C18:3n6; C18:3n3; polyunsaturated fatty acid; and long-chain fatty acids and reduction of C11; C12; C14; ω6/ω3; and atherogenicity index in milk fat.

Histological and physical-mechanical characteristics of the skin of Dorper sheep related to residual feed intake and the confinement environment.

The aim was to evaluate the effect of residual feed intake (RFI) on the histological, physical and mechanical characteristics of the sheep skin confined in full sun or shade. Dorper sheep (n = 64), male, with an initial bodyweight of 17.8 ± 2.43 kg was confined for 40 days to determine the RFI. After classification, 30 animals with positive RFI and 30 animals with negative RFI were selected, which were distributed in 2 confinement environments. This was a factorial arrangement of 2 (groups of animals-positive RFI and negative RFI) × 2 (environments-full sun and shade), with 15 animals for each combination of factors. The sheep remained in confinement for 60 days. After slaughter, skins were divided in half, and fragments were collected from the right portion for histological sections. The left part of each skin was subjected to tanning. Interaction effect RFI × environment was found in the evaluation of leather fragments in the horizontal direction on elongation at break, leather thickness and tear strength (p < 0.05). An isolated effect of the environment was found on elongation at break of leather fragments in the evaluation on the vertical direction (p = 0.01) and on the number of secondary follicles during the histological evaluation of the dorsal and lateral regions of the skin (p < 0.05). An effect of the interaction RFI × environment was observed for the thermostatic layer of the hip region (p = 0.03). Sheep with positive RFI and kept in confinement in full sun have a leather with greater elongation at break and tear strength, important aspects in determining the quality of the product by the leather industry.

Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.

The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.

Tannin as a modulator of rumen microbial profile, apparent digestibility and ingestive behavior of lactating goats: A preliminary metagenomic view of goats adaptability to tannin.

The aim with this study was to use interdisciplinary techniques and visions in order to identify the modulating effect of tannins on adaptive factors in lactating goats with different genetic patterns, through the assessment of digestibility and nutrient intake, ingestive behavior and rumen metagenome. We used in this study 8 of the Repartida ecotype and 6 of the Canindé breed goats, on average five years old, distributed in a completely randomized design, in a 2 × 2 factorial design, with two genetic groups and two diets. The applied diets were: basal diet and inclusion of 5% commercial tannin extract in basal diet. Intake and apparent digestibility of nutrients were evaluated, based on the quantification of the offered feed and refusals, and bromatological evaluation of samples of the offered feed, refusals and feces. Behavioral data were collected in 24-h continuous visual observations. The ruminal fluid was collected and DNA extraction, sequencing, and evaluation of relative abundance of the rumen microbiome were performed. The data obtained were analyzed statistically, through analysis of variance with 5% significance and, when necessary, a comparison of means test was applied. In this preliminary findings was observed that the genetic group factor caused changes in the number of chews and the relative abundance of microorganisms (P = 0.0290 and P = 0.0051). The diet factor influenced digestibility, which better values were observed for the tannin diet (P = 0.0049), in addition, it promoted changes in the rumen microbiota, with a beneficial modulatory characteristic. The inclusion of 5% tannin extract from Acacia mearnsii modulates the rumen microbiome, improving the apparent digestibility of nutrients without affecting the feed intake of goats from the Repartida and Canindé genetic groups.

Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status.

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.