RESUMO
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.
Assuntos
Azacitidina , Leucemia Mieloide Aguda , Humanos , Azacitidina/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Doença Crônica , Antimetabólitos/uso terapêuticoRESUMO
The condition commonly referred to as long coronavirus disease (COVID) is characterized by the continuation of symptoms, sometimes accompanied by new symptoms that persist after the resolution of acute coronavirus disease 2019 (COVID-19). This observational cross-sectional study investigated 332 patients with long COVID in the Brazilian Amazon region. The study aimed to elucidate the systemic interactions associated with long COVID by compiling the findings related to hematological, coagulation, immunological, metabolic, hepatic, renal, and muscular profiles. Participants with long COVID were identified using rigorous criteria and underwent thorough laboratory examinations. The obtained data were subsequently analyzed, allowing for comparisons, associations, and correlations between findings within distinct groups in the study. Significant associations were observed between hospitalization during the acute phase and persistent laboratory abnormalities, suggesting a potential link between acute severity and long-term effects. Notably, individuals with long COVID for over a year exhibited elevated levels of monocytes, prolonged prothrombin times, reduced prothrombin activity, high levels of lactate dehydrogenase, and an increased frequency of qualitative C-reactive protein detection. This study provides valuable insights into the laboratory risk profile of patients with long COVID, particularly in the unique context of the Amazon region, where patients exhibit persistent symptoms lasting up to 1261 days.
Assuntos
COVID-19 , Humanos , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/diagnóstico , Brasil/epidemiologia , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , SARS-CoV-2 , Hospitalização/estatística & dados numéricos , Proteína C-Reativa/análise , Idoso de 80 Anos ou maisRESUMO
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.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Antimetabólitos , Azacitidina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/tratamento farmacológico , Prognóstico , Recidiva , Indução de RemissãoRESUMO
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.
Assuntos
Leucemia Mieloide Aguda , Proteínas Nucleares , Azacitidina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Neoplasia Residual , Proteínas Nucleares/genética , Nucleofosmina , Prognóstico , Proteínas Tirosina Quinases/genética , Recidiva , Indução de Remissão , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
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.
Assuntos
Azacitidina , Leucemia Mieloide Aguda , Animais , Camundongos , Humanos , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Antígenos CD34/metabolismo , Leucemia Mieloide Aguda/genética , Peroxidase , Células-Tronco/metabolismoRESUMO
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.
Assuntos
Ração Animal , Ingestão de Alimentos , Ovinos , Animais , Masculino , Ração Animal/análise , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Dieta/veterináriaRESUMO
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.
Assuntos
Ração Animal , Ingestão de Alimentos , Animais , Masculino , Ração Animal/análise , Dieta/veterinária , Ingestão de Alimentos/fisiologia , Comportamento Alimentar , Nitrogênio/metabolismo , Ovinos , Carneiro DomésticoRESUMO
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.
Assuntos
Pele , Animais , Masculino , Feminino , Carneiro Doméstico/fisiologia , Carneiro Doméstico/crescimento & desenvolvimento , Fatores Sexuais , Privação de Alimentos/fisiologia , Ração Animal/análise , Ovinos/fisiologia , Ovinos/crescimento & desenvolvimento , Orquiectomia/veterináriaRESUMO
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.
Assuntos
Medula Óssea , Leucemia Mieloide Aguda , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos/uso terapêutico , Antígenos CD34 , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Microambiente TumoralRESUMO
Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Linfoma de Células T Periférico/genética , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Resultado do TratamentoRESUMO
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.
RESUMO
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.
Assuntos
Ingestão de Alimentos , Pele , Ração Animal/análise , Animais , Peso Corporal , Dieta/veterinária , Comportamento Alimentar , Masculino , OvinosRESUMO
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.
Assuntos
Leite , Proantocianidinas , Animais , Feminino , Ração Animal/análise , Dieta/veterinária , Ácidos Graxos , Cabras , Lactação , RúmenRESUMO
The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Cutibacterium spp. play an increasing role in soft tissue and implant-associated infections. We isolated a novel Cutibacterium spp. from an implant and investigated this isolate using multiple identification approaches. Correct identification was hampered by inconsistent reference data. The isolate was characterised using conventional methods such as Gram stain, MALDI-TOF MS, and antimicrobial susceptibility testing against multiple antimicrobials. Partial 16S rRNA gene sequencing and whole genome sequencing were also performed. In addition, we summarised the available published sequence data and compared prior data to our strain. Conventional phenotypic identification of our isolate resulted in Cutibacterium spp. After analysis of 16S rRNA gene and genome sequences, our isolate was identified as C. modestum, a very recently described species. The 16S rRNA gene analysis was hampered by three incorrect nucleotides within the 16S rRNA gene reference sequence of C. modestum M12T (accession no. LC466959). We also clearly demonstrate that this novel species is identical to tentatively named "Propionibacterium humerusii". Retrospective data analysis indicates that C. modestum is a clinically important Cutibacterium species often misidentified as C. acnes. The isolation and identification of Cutibacterium spp. is still a challenge. The correct description of very recently named C. modestum and the availability of a correct 16S rRNA sequence of the type strain may help to clarify the taxonomical uncertainty concerning "P. humerusii". The novel C. modestum is an additional, clinically important species within the genus Cutibacterium and may represent a new member of the human skin microbiome.
Assuntos
Acne Vulgar , Propionibacterium acnes , Humanos , Filogenia , Propionibacterium acnes/genética , RNA Ribossômico 16S/genética , Estudos RetrospectivosRESUMO
Passion fruit (Passiflora cincinnata Mast.) is a native fruit from the Caatinga, a typical ecoregion in northeastern Brazil, and it has potential for use by the food and pharmaceutical industries. In this study, we characterized the antimicrobial activity of P. cincinnata and its application in the production of coalho cheese, a traditional Brazilian product. Aqueous extract of P. cincinnata exhibited high inhibitory activity against Listeria spp. (n = 4, reference strains), Staphylococcus aureus (n = 3, reference strains), and multidrug-resistant Staph. aureus (n = 8), and low inhibitory activity against lactic acid bacteria (LAB, n = 3, reference strains). Based on these results, we produced coalho cheese using goat milk with and without (control) passion fruit. Cheeses were stored at 10°C for 14 d and populations of mesophilic aerobes, Staph. aureus, and presumptive LAB were monitored at d 1, 7 and 14. The passion fruit cheese had lower counts of mesophilic aerobes, Staph. aureus (after 7 and 14 d), and presumptive LAB (after 14 d) than the control cheese. Adding ground passion fruit contributed to a reduction of Staph. aureus counts in goat cheese, although these differences were not significant. These results indicated the inhibitory potential of passion fruit and its potential use for controlling microbial populations in a cheese model; further studies are needed to characterize the active molecules that are responsible for such activity.
Assuntos
Queijo/análise , Leite/microbiologia , Passiflora/química , Animais , Brasil/epidemiologia , Microbiologia de Alimentos , Frutas/química , Cabras , Staphylococcus aureus/isolamento & purificaçãoRESUMO
The aim of this study was to evaluate the effect of association of forage cactus meal (CM) and cunhã hay (CH) on carcass traits, meat quality, and fatty acid (FA) profile of goats. Twenty-four goats were finished on diets composed with the association of CM and CH (83% CH + 17% CM, 67% CH + 33% CM, or 50% CH + 50% CM), corresponding to 60% of the total diet; the remainder was composed of 10% elephant grass and 30% concentrate. The control treatment consisted of 70% elephant grass and 30% concentrate. Carcass yield and commercial cut weight were higher in the animals fed CH and CM at any concentration (P < 0.05). Animals fed with intermediate and high CM content resulted in meat with better proportions of unsaturated FA (P = 0.0281), desirable FA (P = 0.0024), omega 6/omega 3 ratio (P = 0.0340), and hypo-/hypercholesterolemic index (P = 0.0140). The inclusion of CH and CM provided carcass yield and FA profile more favorable for consumer market and human health.
Assuntos
Clitoria , Dieta/veterinária , Ácidos Graxos/análise , Cabras , Opuntia , Ração Animal/análise , Animais , Peso Corporal , Ácidos Graxos Insaturados , Masculino , Carne/análiseRESUMO
The aim of this study was to evaluate the effect of adding different concentrations of either urea or NaOH in dehydrated acerola (Malpighia emarginata) fruit residue (DAFR) on chemical composition, in vitro rumen degradability, and gas and methane production. A completely randomized design was used with the following seven treatments: control, without chemical treatment, or pretreatment of DAFR with urea or NaOH at 20, 40, or 60 g/kg dry matter (DM). DM degradability and gas and methane production of DAFR were evaluated by semi-automated in vitro gas production technique. DAFR treated with urea or NaOH at concentrations of 40 and 60 g/kg DM decreased its neutral detergent fiber (P = 0.0115) and lignin (P < 0.0001) content, and this reduction was greater with the highest concentration (60 g/kg DM). In all tested concentrations, urea and NAOH were effective to increase the DM effective degradability of DAFR compared with the control treatment, although treatments with a concentration of 60 g/kg DM presented the highest values (P < 0.0001). Treatment of DAFR with NaOH or urea at 60 g/kg DM promotes greater lignin solubilization and DM degradability and lower gas and methane production in in vitro rumen fermentation.
Assuntos
Digestão , Malpighiaceae/química , Metano/biossíntese , Rúmen/metabolismo , Hidróxido de Sódio/química , Ureia/química , Ração Animal/análise , Animais , Brasil , Dieta/veterinária , Digestão/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fermentação , Frutas/química , Técnicas In Vitro , Masculino , Distribuição Aleatória , Carneiro DomésticoRESUMO
Bean meal (Phaseolus vulgaris L.) may be a viable alternative in ruminant feeding, mainly as a source of protein due to its high crude protein content. The aim of this study was to evaluate the effect of substitution of cottonseed cake (Gossypium hirsutum) with different levels of bean meal in goat feedlot rations on dry matter intake, digestibility, feeding behavior, performance, carcass characteristics, and hematological parameters. Twenty castrated male Repartida goats with an average initial weight of 14.7 ± 2.0 kg were allocated in a randomized block design with four treatments. The initial body weight was used to define the blocks. The treatments were different substitution levels of cottonseed cake by bean meal (0, 27.75, 64.63, and 100%) in the concentrate on a dry matter basis. The diets had a roughage:concentrate ratio of 50:50. Chopped elephant grass (Pennisetum purpureum) was used as roughage, while the concentrate was composed of ground corn, mineral mix, and different levels of bean meal and cottonseed cake. There were no treatment effects on dry matter intake, feed conversion, slaughter weight, carcass weight and yield, non-carcass component yield, and hematological parameters (P > 0.05). However, for both dry matter digestibility (P = 0.001) and daily weight gain (P < 0.001), there was a negative quadratic relationship between cottonseed cake and bean meal content in the diet. Bean meal can be used in goat diets to replace cottonseed cake as the only source of protein concentrate, since it did not affect the main performance characteristics.