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Exploring the contribution of common microorganisms to spoilage is of great significance in inhibiting spoilage in lamb. This work investigated the extent of protein degradation and profile changes of free amino acids (FAAs), free fatty acids (FFAs) and volatile organic compounds (VOCs) in lamb caused by single- and co-culture of the common aerobic spoilage bacteria, P. paralactis, Ac. MN21 and S. maltophilia. Meanwhile, some key VOCs produced by the three bacteria during lamb spoilage were also screened by orthogonal partial least square discriminant analysis and difference value in VOCs content between inoculated groups and sterile group. Lamb inoculated with P. paralactis had the higher total viable counts, pH, total volatile base nitrogen and TCA-soluble peptides than those with the other two bacteria. Some FAAs and FFAs could be uniquely degraded by P. paralactis but not Ac. MN21 and S. maltophilia, such as Arg, Glu, C15:0, C18:0 and C18:1n9t. Co-culture of the three bacteria significantly promoted the overall spoilage, including bacterial growth, proteolysis and lipolysis. Key VOCs produced by P. paralactis were 2, 3-octanedione, those by Ac. MN21 were 1-octanol, octanal, hexanoic acid, 1-pentanol and hexanoic acid methyl ester, and that by S. maltophilia were hexanoic acid. The production of extensive key-VOCs was significantly and negatively correlated with C20:0, C23:0 and C18:ln9t degradation. This study can provide a basis for inhibiting common spoilage bacteria and promoting high-quality processing of fresh lamb.
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Acinetobacter , Técnicas de Cocultura , Microbiologia de Alimentos , Pseudomonas , Carne Vermelha , Stenotrophomonas maltophilia , Compostos Orgânicos Voláteis , Animais , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/metabolismo , Pseudomonas/metabolismo , Pseudomonas/crescimento & desenvolvimento , Acinetobacter/crescimento & desenvolvimento , Acinetobacter/metabolismo , Stenotrophomonas maltophilia/crescimento & desenvolvimento , Stenotrophomonas maltophilia/metabolismo , Carne Vermelha/microbiologia , Carne Vermelha/análise , Ovinos , Armazenamento de Alimentos , Temperatura Baixa , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos não Esterificados/análise , Aminoácidos/metabolismo , Aminoácidos/análise , Carneiro Doméstico/microbiologia , ProteóliseRESUMO
In this study, the effect of different intensity electrostatic fields on the water holding capacity (WHC) of fresh meat during the early postmortem period in controlled freezing point storage (CFPS) were investigated. Significantly lower cooking loss were found in low voltage electrostatic field (LVEF) and high voltage electrostatic field (HVEF) compared to the control group (CK) (p < 0.05). The myofibril fragmentation index and microstructure results suggested that the sample under HVEF treatment remained relatively intact. It has been revealed that the changes in actomyosin properties under electrostatic field treatment groups were due to the combination and dissociation of actomyosin binding into myofilament concentration, which consequently affects the muscle WHC. The study further demonstrated that the electrostatic field, especially HVEF, might increase the WHC of fresh meat by affecting the distribution of water molecules and physiochemical properties of actomyosin during the early postmortem period.
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Actomiosina , Água , Congelamento , Eletricidade Estática , Carne/análise , MiofibrilasRESUMO
Image feature detection serves as the cornerstone for numerous vision applications, and it has found extensive use in agricultural harvesting. Nevertheless, determining the optimal feature extraction technique for a specific situation proves challenging, as the Ground Truth correlation between images is exceedingly elusive in harsh agricultural harvesting environments. In this study, we assemble and make publicly available the inaugural agricultural harvesting dataset, encompassing four crops: rice, corn and soybean, wheat, and rape. We develop an innovative Ground Truth-independent feature detector assessment approach that amalgamates efficiency, repeatability, and feature distribution. We examine eight distinct feature detectors and conduct a thorough evaluation using the amassed dataset. The empirical findings indicate that the FAST detector and ASLFeat yield the most exceptional performance in agricultural harvesting contexts. This evaluation establishes a trustworthy bedrock for the astute identification and application of feature extraction techniques in diverse crop reaping situations.
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Traditional Chinese medicine (TCM) possesses unique advantages in the management of blood glucose and lipids. However, there is still a significant gap in the exploration of its pharmacologically active components. Integrated strategies encompassing deep-learning prediction models and active validation based on absorbable ingredients can greatly improve the identification rate and screening efficiency in TCM. In this study, the affinity prediction of 11,549 compounds from the traditional Chinese medicine system's pharmacology database (TCMSP) with dipeptidyl peptidase-IV (DPP-IV) based on a deep-learning model was firstly conducted. With the results, Gardenia jasminoides Ellis (GJE), a food medicine with homologous properties, was selected as a model drug. The absorbed components of GJE were subsequently identified through in vivo intestinal perfusion and oral administration. As a result, a total of 38 prototypical absorbed components of GJE were identified. These components were analyzed to determine their absorption patterns after intestinal, hepatic, and systemic metabolism. Virtual docking and DPP-IV enzyme activity experiments were further conducted to validate the inhibitory effects and potential binding sites of the common constituents of deep learning and sequential metabolism. The results showed a significant DPP-IV inhibitory activity (IC50 53 ± 0.63 µg/mL) of the iridoid glycosides' potent fractions, which is a novel finding. Genipin 1-gentiobioside was screened as a promising new DPP-IV inhibitor in GJE. These findings highlight the potential of this innovative approach for the rapid screening of active ingredients in TCM and provide insights into the molecular mechanisms underlying the anti-diabetic activity of GJE.
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Aprendizado Profundo , Inibidores da Dipeptidil Peptidase IV , Gardenia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Gardenia/química , Glicosídeos Iridoides/química , Dipeptidil Peptidases e Tripeptidil Peptidases , Dipeptidil Peptidase 4 , Simulação de Acoplamento MolecularRESUMO
In order to extend the shelf life of refrigerating raw lamb by inhibiting the growth of microorganisms, preventing the oxidation of fat and protein, and absorbing the juice outflow of lamb during storage, an active packaging system based on plastic/gelatin bilayer film with essential oil was developed in this study. Three kinds of petroleum-derived plastic films, oriented polypropylene (OPP), polyethylene terephthalate, and polyethylene, were coated with gelatin to make bilayer films for lamb preservation. The results showed significant improvement in the mechanical properties, oxygen, moisture, and light barriers of the bilayer films compared to the gelatin film. The OPP/gelatin bilayer film was selected for further experiments because of its highest acceptance by panelists. If the amount of juice outflow was less than 350% of the mass of the gelatin layer, it was difficult for the gelatin film to separate from lamb. With the increase in essential oil concentration, the water absorption capacity decreased. The OPP/gelatin bilayer films with 20% mustard or 10% oregano essential oils inhibited the growth of bacteria in lamb and displayed better mechanical properties. Essential oil decreased the brightness and light transmittance of the bilayer films and made the film yellow. In conclusion, our results suggested that the active packaging system based on OPP/gelatin bilayer film was more suitable for raw lamb preservation than single-layer gelatin film or petroleum-derived plastic film, but need further study, including minimizing the amount of essential oil, enhancing the mechanical strength of the gelatin film after water absorption.
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Existed methods for 3D object detection in monocular images focus mainly on the class of rigid bodies like cars, while more challenging detection like the cyclist is less studied. Therefore, we propose a novel 3D monocular object detection method to improve the accuracy of detection objects with large differences in deformation by introducing the geometric constraints of the object 3D bounding box plane. Considering the map relationship of projection plane and the keypoint, we firstly introduce the geometric constraints of the object 3D bounding box plane, adding the intra-plane constraint while regressing the position and offset of the keypoint itself, so that the position and offset error of the keypoint are always within the error range of the projection plane. For the inter-plane geometry relationship of the 3D bounding box, the prior knowledge is incorporated to optimize the keypoint regression allowing for improved the accuracy of depth location prediction. Experimental results show that the proposed method outperforms some other state-of-the-art methods on cyclist class, and obtains competitive results in the field of real-time monocular detection.
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Chrysanthemum morifolium Ramat. is a kind of food and drug dual-use traditional Chinese medicine possessing multiple pharmacological and biochemical benefits. In our study, a rapid and high-throughput method based on Surface plasmon resonance (SPR) biosensor technology was developed and verified for screening potential xanthine oxidase (XOD) inhibitors exemplarily in the Chrysanthemum morifolium Ramat. Coupled with ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS), 14 XOD-binders were identified. In the SPR-based biosensor and molecular docking analysis, most compounds exhibited a strong affinity and binding kinetic property (association rate constant, Kon and dissociation rate constant, Koff) for XOD and could be regarded as potential inhibitors. More importantly, to further accurately assess target occupancy of candidate compounds in vivo, a mathematical model was established and verified involving three crucial intrinsic kinetic processes (Pharmacokinetics, Binding kinetic and Target kinetic). Overall, the proposed screening and assessment strategy could be proved an effective theoretical basis for further pharmacodynamic evaluation.
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Chrysanthemum , Xantina Oxidase , Chrysanthemum/química , Simulação de Acoplamento Molecular , Cinética , Cromatografia Líquida de Alta Pressão/métodos , Inibidores EnzimáticosRESUMO
The shrinkage of the connective tissue and myofiber of lamb meat submitted to heat treatment or air drying at different storage stages (1, 5 and 7 days) was evaluated herein. The longitudinal and transverse shrinkage of heated lamb meat was significantly influenced by storage time and water bath heating temperature (50 °C, 70 °C and 90 °C) (p < 0.001). In contrast, the shrinkage of air-dried lamb meat was not influenced by storage time (p > 0.05). The microstructure of heated lamb meat, namely, the distance between muscle fascicles, the distance between myofibril networks, the area of myofibril networks, and the endomysium circumference, was significantly influenced by storage time (p < 0.05). During storage, the proportion of muscle fibers completely detached from endomysium increased, which could be due to the progressive degradation of proteins linking the endomysium and myofibril, including ß-dystroglycan, α-dystroglycan, integrin-ß1, and dystrophin. However, degradation of such proteins did not influence the shrinkage of lamb meat stored for five days or longer, since the decreased distance between myofibril networks indicated a higher shrinkage ratio of the endomysium compared to myofibers in samples air-dried at 35 °C or heated at 90 °C. The effect of these proteins on the shrinkage of heated lamb meat (raw meat stored for 1 day or less time) requires further elucidation.
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INTRODUCTION: Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. METHODS: We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). RESULTS: Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS: Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Terapia Neoadjuvante/métodos , Sunitinibe/uso terapêutico , Adulto , Idoso , Feminino , Seguimentos , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Pulmonary vascular remodeling and fibrosis are the critical pathological characteristics of hypoxic pulmonary hypertension. Our previous study demonstrated that hypoxia is involved in the functional alteration of lung fibroblasts, but the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the effect of mast cells on the proliferation, function and phenotype of fibroblasts under hypoxic conditions. Hypoxia facilitated proliferation and the secretion of proinflammatory cytokines, including tumor necrosis factor (TNF)α and interleukin (IL)6, in human mast cells (HMC1). RNA sequencing identified 2,077 upregulated and 2,418 downregulated mRNAs in human fetal lung fibroblasts (HFL1) cultured in hypoxic conditioned medium from HMC1 cells compared with normoxic controls, which are involved in various pathways, including extracellular matrix organization, cell proliferation and migration. Conditioned medium from hypoxic HMC1 cells increased the proliferation and migration capacity of HFL1 and triggered phenotypic transition from fibroblasts to myofibroblasts. A greater accumulation of collagen type I and III was also observed in an HFL1 cell culture in hypoxic conditioned medium from HMC1 cells, compared with HFL1 cells cultured in normoxic control medium. The expression of matrix metalloproteinase (MMP)9 and MMP13 was upregulated in HFL1 cells grown in hypoxic conditioned medium from HMC1 cells. Similar pathological phenomena, including accumulation of mast cells, activated collagen metabolism and vascular remodeling, were observed in a hypoxic rat model. The results of the present study provide direct evidence that the multiple effects of the hypoxic microenvironment and mast cells on fibroblasts contribute to pulmonary vascular remodeling, and this process appears to be among the most important mechanisms underlying hypoxic pulmonary hypertension.
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Colágeno/metabolismo , Fibroblastos/metabolismo , Hipóxia/metabolismo , Mastócitos/metabolismo , Fenótipo , Biomarcadores , Hipóxia Celular , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Humanos , Imunofenotipagem , Pulmão , Mastócitos/imunologiaRESUMO
Immunotherapy is considered one of the most promising treatments for lung cancer. The cell signalling molecules melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I protein (RIGI) are essential receptors that recognise intracellular pathogen-associated nucleic acids, whereas interferon regulatory factor 3 (IRF3) controls the expression of innate immunity-associated genes in macrophages. However, the innate immune response to polyinosinic:polycytidylic acid [Poly(I:C)] in lung cancer remains to be elucidated. In the present study, western blot analysis, reverse transcription-quantitative polymerase chain reaction, RNA interference, IRF3 plasmid construction, ELISA and apoptosis analysis were employed to study the innate immune response and apoptosis of nonsmall cell lung cancer (NSCLC) cells. Poly(I:C) transfection in NSCLC cells triggered apoptosis via the extrinsic apoptotic pathway, and activated the innate immune response by promoting interferon-ß and C-X-C motif chemokine ligand 10 expression. Treatment with the IκB kinase ε/tumour necrosis factor receptor-associated factor family member-associated nuclear factor-κB activator-binding kinase 1 inhibitor BX795, which inhibits IRF3 phosphorylation, or transfection with small interfering RNA/short hairpin RNA to downregulate MDA5, RIGI or IRF3, prior to Poly(I:C) transfection inhibited the innate immune response and apoptotic pathway. Conversely, IRF3 overexpression promoted activation of the apoptotic pathway, thus indicating that the MDA5/RIGI/IRF3 axis may mediate responses to Poly(I:C) transfection. Furthermore, phosphorylation of the transcription factor signal transducer and activator of transcription 1 (STAT1) was associated with the alterations in IRF3 phosphorylation and apoptosis, thus suggesting that STAT1 may be involved in Poly(I:C)-induced apoptosis. In NSCLC surgical samples, MDA5, RIGI and IRF3 were highly expressed, whereas the expression levels of phosphorylatedIRF3 were reduced. These findings indicated that the function of the MDA5/RIGI/IRF3 axis may be impaired in some lung cancers. In conclusion, the present findings suggested that the MDA5/RIGI/IRF3 axis, which is associated with innate immunity, is intact in NSCLC cells, and IRF3 is involved in regulating the apoptotic pathway in NSCLC cells.
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The present study was designed to examine whether hypoxia induces the proliferation, migration and differentiation of pulmonary arterial fibroblasts (PAFs) via the PI3K/Akt/p70S6K signaling pathway. PAFs were subjected to normoxia (21% O2) or hypoxia (1% O2). The proliferation, migration, differentiation and cellular p110α, pAkt, and pp70S6K expression levels of the PAFs were examined in vitro. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and right ventricular weight/body weight ratio (RV/BW) were examined. The expression levels of p110α, pAkt, p70S6K, fibronectin and αSMA in the rat pulmonary vessels were also examined. Hypoxia significantly elevated the proliferation, migration and differentiation of rat PAFs. It also strongly elevated the expression of p110α, pAkt and pp70S6K in PAFs in vitro. NVPBEZ235 was revealed to significantly reduce the hypoxiainduced proliferation, migration and differentiation. In vivo experiments demonstrated that hypoxia significantly induced the elevation of RVSP, RVHI, RV/BW, medial thickening, adventitious thickening, and fibronectin and collagen deposition around pulmonary artery walls. The expression of p110α, pAkt and p70S6K was evident in the pulmonary arteries of the hypoxic rats. NVPBEZ235 significantly reduced the hypoxiainduced hypoxic pulmonary vascular remodeling, as well as fibronectin and collagen deposition in the pulmonary arteries. Therefore, hypoxia was demonstrated to induce the proliferation, migration and differentiation of PAFs and the hypoxic pulmonary vascular remodeling of rats via the PI3K/Akt/p70S6K signaling pathway.
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Fibroblastos/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Remodelação Vascular , Animais , Diferenciação Celular , Hipóxia Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Masculino , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.
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Indutores da Angiogênese/sangue , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/terapia , Doença Aguda , Adulto , Idoso , Estudos de Casos e Controles , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To determine the underlying histopathologic features influencing apparent diffusion coefficient (ADC) values of breast fibroadenomas. MATERIALS AND METHODS: Biopsy-proven fibroadenomas (n=26) initially identified as suspicious on breast magnetic resonance imaging (MRI) were retrospectively evaluated. Histopathologic assessments of lesion cellularity and stromal type were compared with ADC measures on diffusion-weighted MRI. RESULTS: Presence of epithelial hyperplasia (increased cellularity) and dense collagenous stroma were both significantly associated with lower lesion ADC values (P=.02 and .004, respectively). CONCLUSION: Variations in epithelial cellularity and stromal type influence breast lesion ADC values and may explain the wide range of ADC measures observed in benign fibroadenomas.
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Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Fibroadenoma/diagnóstico por imagem , Adulto , Idoso , Biópsia , Mama/patologia , Neoplasias da Mama/patologia , Reações Falso-Positivas , Feminino , Fibroadenoma/patologia , Humanos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: To determine whether a semiautomated voxel selection technique improves interreader reproducibility for breast apparent diffusion coefficient (ADC) measurements. METHODS: Three readers retrospectively performed ADC measurements of 31 breast lesions (16 malignant, 15 benign) and contralateral normal tissue in 26 women both unassisted (manual method) and assisted by a semiautomated software tool that excludes voxels below a dynamically specified signal intensity threshold. Reproducibility between readers for each technique was assessed by Bland-Altman analysis and concordance correlation coefficients (CCCs). RESULTS: Differences between readers' measured ADCs of lesions were smaller with the semiautomated tool vs the manual method. Concordance correlation coefficients for each reader pair were greater with the semiautomated tool for lesions (mean CCC difference, 0.11; 95% confidence interval, 0.04-0.26). For normal tissue, reader agreement was lower than for lesions and did not differ based on software tools (mean CCC difference, 0.00; 95% confidence interval, -0.14 to 0.13). CONCLUSIONS: A semiautomated voxel selection tool can improve interreader reproducibility of breast lesion ADC measures.
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Neoplasias da Mama/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/normas , Aumento da Imagem/métodos , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Aprendizado de Máquina , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reconhecimento Automatizado de Padrão , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carga TumoralRESUMO
PURPOSE: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. EXPERIMENTAL DESIGN: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m(2) day 1) and vinorelbine (25 mg/m(2) days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response. RESULTS: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1-6.7). CONCLUSIONS: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer. Clin Cancer Res; 22(12); 2855-64. ©2016 AACR.
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Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA2/genética , Benzimidazóis/uso terapêutico , Cisplatino/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Ubiquitina-Proteína Ligases/genética , Vimblastina/análogos & derivados , Adulto , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Reparo do DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Poli Adenosina Difosfato Ribose/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Vimblastina/efeitos adversos , Vimblastina/farmacocinética , Vimblastina/uso terapêutico , VinorelbinaRESUMO
PURPOSE: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. RESULTS: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. CONCLUSIONS: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.
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Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Rituximab/uso terapêutico , Esclerose/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto JovemRESUMO
Chronic graft-versus-host disease (GVHD) is a pleotropic syndrome that lacks validated methods of measuring response in clinical trials, although several end points have been proposed. To investigate the prognostic significance of these proposed end points, such as the 2005 National Institutes of Health (NIH) response measures, 2014 NIH response measures, clinician-reported response, and patient-reported response, we tested their ability to predict subsequent overall survival (OS), nonrelapse mortality (NRM), and failure-free survival (FFS). Patients (n = 575) were enrolled on a prospective chronic GVHD observational trial. At 6 months, clinician-reported response (P = .004) and 2014 NIH-calculated response (P = .001) correlated with subsequent FFS, and clinician-reported response predicted OS (P = .007). Multivariate models were used to identify changes in organ involvement, laboratory values, and patient-reported outcomes that were associated with long-term outcomes. At 6 months, a change in the 2005 NIH 0 to 3 clinician-reported skin score and 0 to 10 patient-reported itching score predicted subsequent FFS. Change in the Lee skin symptom score and Functional Assessment of Cancer Therapy-Bone Marrow Transplant score predicted subsequent OS. Change in the Lee skin symptom score predicted subsequent NRM. This study provides evidence that clinician-reported response and patient-reported outcomes are predictive of long-term survival. The trial was registered at www.clinicaltrials.gov as #NCT00637689.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Avaliação de Resultados da Assistência ao Paciente , Autorrelato , Índice de Gravidade de Doença , Adulto , Idoso , Doença Crônica , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Estados Unidos , Adulto JovemRESUMO
Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.
Assuntos
Bronquiolite Obliterante , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Adulto , Idoso , Aloenxertos , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/mortalidade , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.