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In present study, whey protein isolate fibrils and sodium alginate complexes (WPIFs-SA) were prepared and further used to stabilize Pickering emulsions for lycopene delivery. The optimal interaction between WPIFs and SA occurred at pH 3.0, with a mass ratio of 2:1. Increasing the oil fractions and the content of WPIFs-SA complexes significantly improved Pickering emulsions' stability, concurrently reducing droplet size and increasing viscoelasticity. Meanwhile, it facilitated the formation of a thicker protective layer and a compact network structure around the oil droplets, offering better protection for lycopene against thermal and photo degradation. In vitro digestion studies revealed that as the oil fractions and complex contents increased, the lipolysis degree decreased. The engineered WPIFs-SA Pickering emulsion could be used as an innovative delivery system for the protection and delivery of lycopene.
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Alginatos , Emulsiones , Licopeno , Proteína de Suero de Leche , Proteína de Suero de Leche/química , Alginatos/química , Licopeno/química , Concentración de Iones de Hidrógeno , Digestión , Viscosidad , Tamaño de la Partícula , Carotenoides/química , Lipólisis , Ácido Glucurónico/química , Ácidos Hexurónicos/químicaRESUMEN
Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower than those of AML without deletion 7/7q, this observation was not significant. Low ASNS expression correlated with improved overall survival (46 versus 54 weeks, respectively, p = 0.011), whereas higher ASNS levels were associated with better response to venetoclax-based therapy. Protein correlation analysis demonstrated association between ASNS and proteins involved in methylation and DNA repair. In conclusion, while ASNS expression was not lower in patients with deletion 7/7q as initially predicted, ASNS levels were highly variable across AML patients. Further studies are needed to assess whether patients with low ASNS expression are susceptible to asparaginase-based therapy due to their inability to augment compensatory ASNS expression upon asparagine depletion.
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Aspartatoamoníaco Ligasa , Leucemia Mieloide Aguda , Proteómica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Aspartatoamoníaco Ligasa/genética , Aspartatoamoníaco Ligasa/metabolismo , Femenino , Proteómica/métodos , Masculino , Persona de Mediana Edad , Adulto , Anciano , Deleción Cromosómica , Análisis por Matrices de Proteínas/métodos , Asparaginasa/uso terapéutico , Asparaginasa/genética , Cromosomas Humanos Par 7/genética , Adulto Joven , Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-NRESUMEN
The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy.
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The use of Hypomethylating agents combined with Venetoclax (VH) for the treatment of Acute Myeloid Leukemia (AML) has greatly improved outcomes in recent years. However not all patients benefit from the VH regimen and a way to rationally select between VH and Conventional Chemotherapy (CC) for individual AML patients is needed. Here, we developed a proteomic-based triaging strategy using Reverse-phase Protein Arrays (RPPA) to optimize therapy selection. We evaluated the expression of 411 proteins in 810 newly diagnosed adult AML patients, identifying 109 prognostic proteins, that divided into five patient expression profiles, which are useful for optimizing therapy selection. Furthermore, using machine learning algorithms, we determined a set of 14 proteins, among those 109, that were able to accurately recommend therapy, making it feasible for clinical application. Next, we identified a group of patients who did not benefit from either VH or CC and proposed target-based approaches to improve outcomes. Finally, we calculated that the clinical use of our proteomic strategy would have led to a change in therapy for 30% of patients, resulting in a 43% improvement in OS, resulting in around 2600 more cures from AML per year in the United States.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Proteómica , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Proteómica/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Femenino , Masculino , Pronóstico , Anciano , Adulto , Metilación de ADN , Anciano de 80 o más Años , Adulto Joven , Tasa de SupervivenciaRESUMEN
BACKGROUND: Butter has been widely used in bakery products and it contains high level of saturated fats. However, excessive consumption of saturated fats would increase the risk of chronic disease. This study was to fabricate water-in-oil (W/O) type bigels as butter replacers to improve the quality attributes of breads. RESULTS: A stable water-in-oil (W/O) type bigel system was fabricated based on mixed oleogelators (rice bran wax and glycerol monostearate) and sodium alginate hydrogel. The ratios of oleogel to hydrogel could significantly affect the stability, microstructure and rheological properties of bigels. All of the bigels exhibited solid-like properties, with increased oleogel fractions, and the network structure of bigel became more compact and orderly with smaller sodium alginate gel particles. Meanwhile, the viscoelastic modulus and firmness of bigel increased, contributing to a higher stability. The bigel dough exhibited lower gel strength and relatively higher extensibility compared to the butter dough. Regardless of oleogel fractions, all the bigel produced bread with a higher specific volume and softer texture than the butter bread. When the oleogel fractions was less than 80%, increasing the oleogel fractions was more beneficial for improving the specific volume, softness and fluffy structure of bread. CONCLUSION: W/O type bigel as butter replacers showed great potential in improving the appearance, structure and textural properties of bread. © 2023 Society of Chemical Industry.
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Pan , Mantequilla , Hidrogeles/química , Alginatos , Agua , Compuestos OrgánicosRESUMEN
The double emulsions-filled hydrogel beads delivery systems with controlled lipolysis and sustained-release property of co-encapsulated bioactive substances will be highly desired. Herein, the water-in-oil-in-water emulsion with gelled inner water phase and oil phase (WG/OG/W) filled hydrogel beads as a novel co-delivery system were developed with varied concentrations of rice bran wax and W/O emulsions to achieve effectively controlled release of lipolysis and nutraceuticals. Interestingly, the gelation of oil phase triggered by rice bran wax could enhance the storage stability of WG/OG/W emulsions due to the enhanced viscoelastic property. Increasing the mass fractions of W/O emulsions improved the stability of double emulsions due to increased viscosity and decreased particle size. Cryo-SEM observation showed that the double emulsion droplets were scattered in the three-dimensional network of alginate gel beads. Increased the addition of rice bran wax or W/O emulsions, the encapsulation efficiency of collagen peptide and astaxanthin was significantly improved. The in vitro digestion results indicated that increasing the concentrations of rice bran wax and W/O emulsion fractions in WG/OG/W emulsion-filled gel beads could effectively delay the release extent of free fatty acids and encapsulated nutraceuticals. The presence of rice bran wax contributed to increase the bioaccessibility of collagen peptide and astaxanthin.
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Alginatos , Hidrogeles , Emulsiones/química , Alginatos/química , Agua/química , Colágeno , Digestión , Tamaño de la PartículaRESUMEN
PURPOSE: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the main mechanisms of ER-mediated cell stress adaptation. Targeting the cell stress response is a promising therapeutic approach in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Protein expression levels of valosin-containing protein (VCP), a chief element of ERAD, were measured in peripheral blood samples from in 483 pediatric AML patients using reverse phase protein array methodology. Patients participated in the Children's Oncology Group AAML1031 phase 3 clinical trial that randomized patients to standard chemotherapy (cytarabine (Ara-C), daunorubicin, and etoposide [ADE]) versus ADE plus bortezomib (ADE+BTZ). RESULTS: Low-VCP expression was significantly associated with favorable 5-year overall survival (OS) rate compared to middle-high-VCP expression (81% versus 63%, p < 0.001), independent of additional bortezomib treatment. Multivariable Cox regression analysis identified VCP as independent predictor of clinical outcome. UPR proteins IRE1 and GRP78 had significant negative correlation with VCP. Five-year OS in patients characterized by low-VCP, moderately high-IRE1 and high-GRP78 improved after treatment with ADE+BTZ versus ADE (66% versus 88%, p = 0.026). CONCLUSION AND CLINICAL RELEVANCE: Our findings suggest the potential of the protein VCP as biomarker in prognostication prediction in pediatric AML.
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Proteínas de Ciclo Celular , Chaperón BiP del Retículo Endoplásmico , Niño , Humanos , Bortezomib/farmacología , Bortezomib/uso terapéutico , Bortezomib/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Respuesta de Proteína Desplegada , Proteína que Contiene Valosina/genética , Proteína que Contiene Valosina/metabolismoRESUMEN
BACKGROUND: Dopamine is a neurotransmitter and has been found to regulate lymphocytes by acting on dopamine receptors (DRs). CD4+ T cells express all the five subtypes of DRs, D1R to D5R. Although CD4+ T cells have been involved in pathogenesis of rheumatoid arthritis (RA), roles of DRs expressed on these cells in RA are poorly understood. This study determined whether D2R expressed on CD4+ T cells regulates inflammatory responses and signs in collagen type II (CII)-induced arthritis (CIA), a mouse model of RA. METHODS: DBA/1 mice and C57BL/6 mice with global D1r or D2r deficiency (D1r-/- or D2r-/-) or CD4+ T cell-specific D2r deletion (D2rfl/fl/CD4Cre) were used to prepare CIA model by intradermal injection of CII. D2R agonist sumanirole was intraperitoneally administered in CIA mice. CD4+ T cells obtained from CIA mice were exposed to sumanirole or/and D2R antagonist L-741,626 in vitro. Arthritic symptoms were assessed by clinical arthritis scores. Flow cytometric assay measured frequencies of CD4+ T cell subsets (Th1, Th2, Th17 and Treg cells). Expression of specific transcription factors for the CD4+ T cell subsets was tested by Western blot. Cytokine production was estimated by quantitative PCR and ELISA. RESULTS: CIA mice manifested a bias of CD4+ T cells towards Th1 and Th17 cells. D2r-/- CIA mice showed a stronger bias towards Th1 and Th17 phenotypes than CIA mice, while D1r-/- CIA mice did not show the changes. CD4+ T cell-specific D2r deletion exacerbated both the polarization towards Th1 and Th17 cells and the symptoms of arthritis. Sumanirole administration in CIA mice ameliorated the bias of CD4+ T cells towards Th1 and Th17 phenotypes as well as arthritic symptoms. Sumanirole treatment of in vitro CD4+ T cells obtained from CIA mice promoted the shift to Treg cells, and the effect of sumanirole was blocked by L-741,626. CONCLUSIONS: D2R expressed on CD4+ T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA.
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Artritis Experimental , Artritis Reumatoide , Receptores de Dopamina D2 , Animales , Ratones , Artritis Experimental/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Receptores de Dopamina D2/metabolismo , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismoRESUMEN
Background: Recent research in our laboratory shows that CD4+ T cells express the ß2 adrenergic receptor (ß2-AR), and the sympathetic neurotransmitter norepinephrine regulates the function of T cells via ß2-AR signaling. However, the immunoregulatory effect of ß2-AR and its related mechanisms on rheumatoid arthritis is unknown. Objective: To explore the effects of ß2-AR in collagen-induced arthritis (CIA) on the imbalance of T helper (Th) 17/ regulatory T (Treg) cells. Methods: In DBA1/J mice, collagen type II was injected intradermally at the tail base to prepare the CIA model. The specific ß2-AR agonist, terbutaline (TBL), was administered intraperitoneally beginning on day 31 and continuing until day 47 after primary vaccination, twice a day. Magnetic beads were used to sort CD3+ T cells subsets from spleen tissues. Results: In vivo, ß2-AR agonist TBL alleviated arthritis symptoms in the CIA mice including histopathology of the ankle joints, four limbs' arthritis score, the thickness of ankle joints, and rear paws. After TBL treatment, in the ankle joints, the levels of proinflammatory factors (IL-17/22) notably decreased and the levels of immunosuppressive factors (IL-10/TGF-ß) significantly increased. In vitro, ROR-γt protein expression, Th17 cell number, mRNA expression and the releasing of IL-17/22 from CD3+ T cells reduced following TBL administration. Moreover, TBL enhanced the anti-inflammatory responses of Treg cells. Conclusion: These results suggest that ß2-AR activation exerts anti-inflammatory effects through the amelioration of Th17/Treg imbalance in the CIA disease.
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Artritis Experimental , Artritis Reumatoide , Animales , Ratones , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Colágeno Tipo II/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Norepinefrina/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Receptores Adrenérgicos/metabolismo , ARN Mensajero/metabolismo , Linfocitos T Reguladores , Terbutalina/farmacología , Células Th17/metabolismo , Factor de Crecimiento Transformador betaRESUMEN
DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.
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Leucemia Linfocítica Crónica de Células B , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Adulto , Niño , Leucemia Mieloide Aguda/genética , Análisis por Matrices de Proteínas , Leucemia Linfocítica Crónica de Células B/genética , Proteínas/genética , Enfermedad Crónica , Daño del ADN/genéticaRESUMEN
Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival outcomes. Patients within clusters C1 and C2 had poorer survival outcomes and responses to fludarabine, cyclophosphamide, and rituxan chemotherapy compared to patients within cluster C3. However, DDR protein expression patterns were not prognostic in more modern therapies with BCL2 inhibitors or a BTK/PI3K inhibitor. Individually, nine of the DDR proteins were prognostic for predicting overall survival and/or time to first treatment. When looking for other proteins that may be associated with or influenced by DDR expression patterns, our differential expression analysis found that cell cycle and adhesion proteins were lower in clusters compared to normal CD19 controls. In addition, cluster C3 had a lower expression of MAPK proteins compared to the poor prognostic patient clusters thus implying a potential regulatory connection between adhesion, cell cycle, MAPK, and DDR signaling in CLL. Thus, assessing the proteomic expression of DNA damage proteins in CLL provided novel insights for deciphering influences on patient outcomes and expanded our understanding of the potential complexities and effects of DDR cell signaling.
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Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteómica , Daño del ADN , Receptores con Dominio Discoidina/genéticaRESUMEN
The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In adult patients, seven DDR proteins were individually prognostic for either RD or OS. When DDR proteins were analyzed together with DDR-related proteins operating in diverse cellular signaling pathways, these expanded groupings were also highly prognostic for OS. Analysis of patients treated with either conventional chemotherapy or venetoclax combined with a hypomethylating agent revealed protein clusters that differentially predicted favorable from unfavorable prognoses within each therapy cohort. Collectively, this investigation provides insight into variable DDR pathway activation in AML and may help direct future individualized DDR-targeted therapies in AML patients.
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Leucemia Mieloide Aguda , Humanos , Adulto , Niño , Pronóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Reparación del ADN/genética , Daño del ADN , Receptores con Dominio Discoidina/genéticaRESUMEN
Two kinds of nanocellulose (cellulose nanofibrils (CNFs) and cellulose nanocrystals (CNCs) were synthesized from pomelo peels via a facile approach of TEMPO oxidation and sulfuric acid treatment respectively. The FTIR results illustrated that hemicelluloses and lignin were completely removed from the pomelo peel cellulose substrate. The obtained CNFs and CNCs possessed a uniform morphology and nanoscale particle size. The stability of CNF-based Pickering emulsions was higher than that of emulsions stabilized with CNCs, due to the formation of gel structure induced by the CNFs' longer fibrils. Increased oil fractions enhanced the viscoelasticity of CNF-based Pickering emulsions. The in vitro digestion results suggested that increased oil fractions decreased the lipolysis degree, as a result of the larger droplet size and higher viscoelasticity of emulsion. The release of lycopene showed a trend similar to that of FFA release, suggesting that higher oil fractions were beneficial for controlling lycopene release during gastrointestinal digestion.
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Celulosa , Nanopartículas , Emulsiones/química , Licopeno , Preparaciones de Acción Retardada , Celulosa/química , Nanopartículas/químicaRESUMEN
Classical hairy cell leukemia (HCL-c) and HCL variant (HCL-v) are recognized as separate entities with HCL-v having significantly shorter overall survival. Proteomic studies, shown to be prognostic in various forms of leukemia, have not been performed in HCL. We performed reverse phase protein array-based protein profiling with 384 antibodies in HCL-c (n = 12), HCL-v (n = 4), and normal B-cells (n = 5) samples. While HCL could be distinguished from normal based on unsupervised hierarchical clustering, overlap in protein expression patterns was seen between HCL-c and HCL-v, with â¼10% of the proteins being differentially expressed, suggesting potential therapeutic targets.
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As the third leading cause of cancer death worldwide, hepatocellular carcinoma (HCC) is characterized by late detection, difficult diagnosis and treatment, rapid progression, and poor prognosis. Current treatments for liver cancer include surgical resection, radiofrequency ablation, liver transplantation, chemotherapy, external radiation therapy, and internal radionuclide therapy. Radionuclide therapy is the use of high-energy radiation emitted by radionuclides to eradicate tumor cells, thus achieving the therapeutic effect. Recently, with the continuous development of biomedical technology, the application of radionuclides in treatment of HCC has progressed steadily. This review focuses on three types of radionuclide-based treatment regimens, including transarterial radioembolization (TARE), radioactive seed implantation, and radioimmunotherapy. Their research progress and clinical applications are summarized. The advantages, limitations, and clinical potential of radionuclide treatment of HCC are discussed.
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Interleukin 17A (IL-17A) was previously shown to be a key pro-inflammatory factor in diabetes mellitus and associated complications. However, the role of IL-17A in diabetic encephalopathy remains poorly understood. In this study, we established a mouse model of diabetic encephalopathy that was deficient in IL-17A by crossing Il17a-/- mice with spontaneously diabetic Ins2Akita (Akita) mice. Blood glucose levels and body weights were monitored from 2-32 weeks of age. When mice were 32 weeks of age, behavioral tests were performed, including a novel object recognition test for assessing short-term memory and learning and a Morris water maze test for evaluating hippocampus-dependent spatial learning and memory. IL-17A levels in the serum, cerebrospinal fluid, and hippocampus were detected with enzyme-linked immunosorbent assays and real-time quantitative polymerase chain reaction. Moreover, proteins related to cognitive dysfunction (amyloid precursor protein, ß-amyloid cleavage enzyme 1, p-tau, and tau), apoptosis (caspase-3 and -9), inflammation (inducible nitric oxide synthase and cyclooxygenase 2), and occludin were detected by western blot assays. Pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1ß, and interferon-γ in serum and hippocampal tissues were measured by enzyme-linked immunosorbent assays. Microglial activation and hippocampal neuronal apoptosis were detected by immunofluorescent staining. Compared with that in wild-type mice, mice with diabetic encephalopathy had higher IL-17A levels in the serum, cerebrospinal fluid, and hippocampus; downregulation of occludin expression; lower cognitive ability; greater loss of hippocampal neurons; increased microglial activation; and higher expression of inflammatory factors in the serum and hippocampus. IL-17A knockout attenuated the abovementioned changes in mice with diabetic encephalopathy. These findings suggest that IL-17A participates in the pathological process of diabetic encephalopathy. Furthermore, IL-17A deficiency reduces diabetic encephalopathy-mediated neuroinflammation and cognitive defects. These results highlight a role for IL-17A as a mediator of diabetic encephalopathy and potential target for the treatment of cognitive impairment induced by diabetic encephalopathy.
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Protein expression for 384 total and post-translationally modified proteins was assessed in 871 CLL and MSBL patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteomics identified six recurrent signatures that were highly prognostic of survival and time to first or second treatment at three levels: individual proteins, when grouped into 40 functionally related groups (PFGs), and systemically in signatures (SGs). A novel SG characterized by hairy cell leukemia like proteomics but poor therapy response was discovered. SG membership superseded other prognostic factors (Rai Staging, IGHV Status) and were prognostic for response to modern (BTK inhibition) and older CLL therapies. SGs and PFGs membership provided novel drug targets and defined optimal candidates for Watch and Wait vs. early intervention. Collectively proteomics demonstrates promise for improving classification, therapeutic strategy selection, and identifying novel therapeutic targets.
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Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Pronóstico , ProteómicaRESUMEN
Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patients' samples and 30 control CD34+ cell samples, using reverse phase protein arrays with 296 strictly validated antibodies. The multistep MetaGalaxy analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIG were associated with cytogenetics and mutational state, and with favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib) identified three PrSIG that did better with ADE plus bortezomib than with ADE alone. When PrSIG were studied in the context of cytogenetic risk groups, PrSIG were independently prognostic after multivariate analysis, suggesting a potential value for proteomics in combination with current classification systems. Proteins with universally increased (n=7) or decreased (n=17) expression were observed across PrSIG. Certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.
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Leucemia Mieloide Aguda , Proteómica , Bortezomib , Niño , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Pronóstico , Análisis por Matrices de Proteínas , ProteínasRESUMEN
The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.
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Epigénesis Genética , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Anciano , Aberraciones Cromosómicas , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Masculino , Persona de Mediana Edad , Mutación , ProteómicaRESUMEN
PURPOSE: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031) . Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. EXPERIMENTAL DESIGN: RelA-total and phosphorylation at serine 536 (RelA-pSer536 ) were measured in 483 patient samples using reverse phase protein array technology. RESULTS: In ADEB-treated patients, low-RelA-pSer536 was favorably prognostic when compared to high-RelA-pSer536 (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). Among low-RelA-pSer536 patients, RR significantly decreased with ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer536 and 295 other assayed proteins identified a strong correlation with HSF1-pSer326 , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer536 and low-HSF1-pSer326 was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). CONCLUSION AND CLINICAL RELEVANCE: Bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326 .