RESUMEN
ABSTRACT: The safety and efficacy of chimeric antigen receptor T-cell therapy is not well described in older patients, a population that has higher frailty and comorbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (aged <65 years) vs older (aged ≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n = 75, aged ≥65 years) were infused with ide-cel by data cutoff. In older patients (median age: 69 years; range, 65-83; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable with pivotal KarMMa study results (ORR: 73%). Median progression-free survival and overall survival in older patients were 9.1 months and 26.5 months, respectively. Grade ≥3 cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were observed in 1% and 4% of older patients, respectively. Compared with younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (≥5 drugs; 97%), ≥4 comorbidities (69%), and organ dysfunction (35%; P < .05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.
Asunto(s)
Mieloma Múltiple , Humanos , Anciano , Masculino , Anciano de 80 o más Años , Femenino , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Resultado del Tratamiento , Estudios Retrospectivos , Productos Biológicos/uso terapéutico , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Factores de EdadRESUMEN
Anti-inflammatory effect of piceatannol, a naturally occurring polyphenol and a potent free radical scavenger, on ocular inflammation is not known. We examined the anti-inflammatory role of piceatannol in ocular inflammatory response due to endotoxin-induced uveitis (EIU) in rats. EIU was induced in Lewis rats by subcutaneous injection of lipopolysaccharide (LPS; 150 ug/rat). Piceatannol (30mg/kg body wt, i.p) was injected either 2h prior to or 1h post LPS induction. A significant increase in the number of infiltrating cells, total protein, and various cytokines and chemokines in AqH were observed in the EIU rat eyes as compared to control groups. However, pre- or post-treatment of piceatannol significantly blocked the LPS-induced changes. Further, piceatannol also suppressed the expression of cyclooxygenase-2 (Cox-2), inducible nitric oxide synthase (iNOS) and activation of NF-κB in the ciliary bodies as well as retina. Further, piceatannol also inhibited the expression of Cox-2, iNOS, and phosphorylation of NF-κB in primary human non-pigmented ciliary epithelial cells (HNPECs) treated with LPS. Similarly, piceatannol also diminished LPS-induced level of NO and prostaglandin E2 in HNPECs. Thus our results demonstrate an anti-inflammatory role of piceatannol in suppressing ocular inflammation induced by endotoxin in rats.
Asunto(s)
Humor Acuoso/efectos de los fármacos , Depuradores de Radicales Libres/administración & dosificación , Retina/inmunología , Choque Séptico/tratamiento farmacológico , Estilbenos/administración & dosificación , Uveítis/tratamiento farmacológico , Animales , Humor Acuoso/inmunología , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Endogámicas Lew , Retina/efectos de los fármacos , Choque Séptico/inmunología , Uveítis/inducido químicamente , Uveítis/inmunologíaRESUMEN
PURPOSE: To investigate the therapeutic effects of metformin, a commonly used antidiabetic drug, in preventing endotoxin-induced uveitis (EIU) in rats. METHODS: EIU in Lewis rats was developed by subcutaneous injection of lipopolysaccharide (LPS; 150 µg). Metformin (300 mg/kg body weight, intraperitoneally) or its carrier was injected either 12 hours before or 2 hours after LPS induction. Three and 24 hours after EIU, eyes were enucleated and aqueous humor (AqH) was collected. The MILLIPLEX-MAG Rat cytokine-chemokine magnetic bead array was used to determine inflammatory cytokines. The expression of Cox-2, phosphorylation of AMPK, and NF-κB (p65) were determined immunohistochemically. Primary human nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of metformin. RESULTS: Compared with controls, the EIU rat AqH had significantly increased number of infiltrating cells and increased levels of various cytokines and chemokines (TNF-α, MCP-1, IL-1ß, MIP-1α, IL-6, Leptin, and IL-18) and metformin significantly prevented the increase. Metformin also prevented the expression of Cox-2 and phosphorylation of p65, and increased the activation of AMPK in the ciliary bodies and retinal tissues. Moreover, metformin prevented the expression of Cox-2, iNOS, and activation of NF-kB in the HNPECs and decreased the levels of NO and PGE2 in cell culture media. CONCLUSIONS: Our results for the first time demonstrate a novel role of the antidiabetic drug, metformin, in suppressing uveitis in rats and suggest that this drug could be developed to prevent uveitis complications.
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Modelos Animales de Enfermedad , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Uveítis/prevención & control , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Humor Acuoso/metabolismo , Western Blotting , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Inyecciones Intraperitoneales , Lipopolisacáridos , Masculino , Fosforilación , Proteínas Quinasas/metabolismo , Ratas , Ratas Endogámicas Lew , Factor de Transcripción ReIA/metabolismo , Uveítis/inducido químicamente , Uveítis/metabolismoRESUMEN
PURPOSE: Recent studies indicate that ethyl pyruvate (EP) exerts anti-inflammatory properties; however, the effect of EP on ocular inflammation is not known. The efficacy of EP in endotoxin-induced uveitis (EIU) in rats was investigated. METHODS: EIU in Lewis rats was developed by the subcutaneous injection of lipopolysaccharide (LPS; 150 µg). EP (30 mg/kg body weight) or its carrier was injected intraperitoneally 1 hour before or 2 hours after lipopolysaccharide injection. Animals were killed after 3 and 24 hours followed by enucleation of eyes and collection of the aqueous humor (AqH). The number of infiltrating cells and levels of proteins in the AqH were determined. The rat cytokine/chemokine multiplex method was used to determine level of cytokines and chemokines in the AqH. TNF-α and phospho-nuclear factor kappa B (NF-κB) expression in ocular tissues were determined immunohistochemically. Human primary nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of EP on lipopolysaccharide-induced inflammatory response. RESULTS: Compared to controls, AqH from the EIU rat eyes had a significantly higher number of infiltrating cells, total protein, and inflammatory cytokines/chemokines, and the treatment of EP prevented EIU-induced increases. In addition, EP also prevented the expression of TNF-α and activation of NF-κB in the ciliary bodies and retina of the eye. Moreover, in HNPECs, EP inhibited lipopolysaccharide-induced activation of NF-κB and expression of Cox-2, inducible nitric oxide synthase, and TNF-α. CONCLUSIONS: Our results indicate that EP prevents ocular inflammation in EIU, suggesting that the supplementation of EP could be a novel approach for the treatment of ocular inflammation, specifically uveitis.
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Piruvatos/uso terapéutico , Uveítis/prevención & control , Animales , Humor Acuoso/metabolismo , Western Blotting , Supervivencia Celular , Células Cultivadas , Cuerpo Ciliar/citología , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Endotoxinas/toxicidad , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Lipopolisacáridos/toxicidad , Masculino , Microscopía Fluorescente , FN-kappa B/metabolismo , Ratas , Ratas Endogámicas Lew , Especies Reactivas de Oxígeno/metabolismo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismo , Uveítis/inducido químicamente , Uveítis/metabolismoRESUMEN
Carotenoids are known to generate various aldehydes, known as carotenoid-derived aldehydes (CDAs), which could efficiently react with protein or DNA. In this in vitro model study, interaction between CDA and protein has been studied. Various proteins were incubated with CDA, and protein modification and adduct formation were confirmed by using matrix-assisted laser desorption and ionization time-of-flight, amino acid analysis, and measuring enzyme activity on modification with CDA. Using radiolabeled NaB((3) H)H(4) and Raney nickel as well as sulfhydryl assay (Ellman's reagent), we confirmed that CDA could conjugate with cysteine through a thioether linkage. The carbonyl assay using 2,4-dinitrophenylhydrazine revealed the possible involvement of Schiff's base reaction between CDA and lysine. The adducts formed between ß-apo-8-carotenal (BA8C) and N-acetylcysteine and BA8C and N-acetyllysine were confirmed by HPLC and ESI-MS. Our results suggest that CDA could alter protein function by post-translational interaction with cysteine and lysine by thioether linkage and by schiff's based bonds, respectively. Thus, the formation of CDA adducts with proteins could alter functional properties of proteins responsible for maintaining cell homeostasis and thereby cause cellular toxicity. In view of these observations, further studies are required to understand the delicate balance between beneficial and/or harmful effects of carotenoids as a dietary supplement to slow age-related macular degeneration progression.
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Carotenoides/química , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas/química , Proteínas/metabolismo , Aldehídos/química , Aldehídos/farmacología , Cromatografía Líquida de Alta Presión , Unión Proteica , Carbonilación Proteica , Bases de Schiff/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Cadmium is reported to accumulate in human eye tissues suggesting its implication in diverse ocular pathology. Using an in vitro cell culture model we investigated the effects of cadmium on human lens epithelial cells (HLECs) (HLE-B3). We observed cadmium-induced dose- as well as time-dependent decline in HLECs viability which was exacerbated significantly upon reduction of intracellular glutathione levels by buthionine sulfoximine (BSO). There was a dose-dependent significant increase in lactate dehydrogenase (LDH) release from HLECs suggesting cadmium-induced alteration of membrane integrity as well as necrotic cell death. The decline in cell viability was also due to apoptosis of the HLECs as determined by quantifying % apoptotic cells as well as PARP cleavage. Moreover, release of apoptosis inducing factor (AIF) into the cytosol was also detected. Cadmium was also observed to increase oxidative stress, lipid peroxidation and activation of MAPK pathway in HLECs. Antioxidants like N-acetylcysteine (NAC) and alpha-Tocopherol significantly prevented cadmium-induced toxicity in HLECs. Our findings suggest that cadmium-induced elevated oxidative stress as well as activation of MAPK signaling cascade eventually led to cell death of HLECs through apoptosis as well as necrosis. The loss of HLECs by cadmium could possibly explain its implication in cataract development particularly associated with smoking.
Asunto(s)
Apoptosis/efectos de los fármacos , Cadmio/toxicidad , Células Epiteliales/efectos de los fármacos , Cristalino/efectos de los fármacos , Catarata/inducido químicamente , Catarata/etiología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/metabolismo , Glutatión/metabolismo , Humanos , Cristalino/citología , Cristalino/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estrés Oxidativo , Transducción de Señal/efectos de los fármacos , Fumar/efectos adversosRESUMEN
PURPOSE: To investigate the anti-inflammatory effects of guggulsterone, an antioxidant and antitumor agent, in endotoxin-induced uveitis (EIU) in rats and to elucidate the underlying molecular mechanism or mechanisms related to ocular inflammation. METHODS: EIU was induced by subcutaneous injection of lipopolysaccharide (LPS; 150 µg) into Lewis rats treated with guggulsterone (30 mg/kg body weight, intraperitoneally) or its carrier. After 24 hours the rats were killed, eyes were enucleated, and aqueous humor (AqH) was collected. Numbers of infiltrating cells and levels of matrix metalloproteinase-2 (MMP-2), nitric oxide (NO), and prostaglandin E(2) (PGE(2)) were determined in AqH by specific ELISAs. An antibody array was used to measure the expression of various inflammatory cytokines in AqH. The expression of MMP-2, iNOS, Cox-2, phospho-IκB, and phospho-NF-κB was determined immunohistochemically. Human primary nonpigment ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of guggulsterone on the LPS-induced inflammatory response. RESULTS: Compared with control, the EIU rat eye AqH had a significantly higher number of infiltrating cells, total protein, and inflammatory markers, such as MMP-2, NO, and PGE(2), and the treatment of guggulsterone prevented EIU-induced increases. Guggulsterone also prevented the expression of MMP-2, iNOS, and Cox-2 proteins and of IκB and NF-κB in various eye tissues. Moreover, in cultured HNPECs, guggulsterone inhibited LPS-induced expression of inflammatory proteins. CONCLUSIONS: These results for the first time demonstrate that the plant sterol guggulsterone suppresses ocular inflammation in EIU, suggesting that the supplementation of guggulsterone could be a novel approach for the treatment of ocular inflammation.
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Antineoplásicos/uso terapéutico , Antioxidantes/uso terapéutico , Commiphora , Modelos Animales de Enfermedad , Lipopolisacáridos , Pregnenodionas/uso terapéutico , Uveítis/prevención & control , Animales , Humor Acuoso/citología , Humor Acuoso/metabolismo , Western Blotting , Células Cultivadas , Cuerpo Ciliar/efectos de los fármacos , Citocinas/metabolismo , Dinoprostona/metabolismo , Ensayo de Inmunoadsorción Enzimática , Escherichia coli , Humanos , Proteínas I-kappa B/metabolismo , Inyecciones Intraperitoneales , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Endogámicas Lew , Uveítis/inducido químicamente , Uveítis/metabolismoRESUMEN
This study was designed to investigate the molecular mechanisms by which benfotiamine, a lipid-soluble analogue of vitamin B1, affects lipopolysaccharide (LPS)-induced inflammatory signals leading to cytotoxicity in the mouse macrophage cell line RAW264.7. Benfotiamine prevented LPS-induced apoptosis, expression of the Bcl-2 family of proapoptotic proteins, caspase-3 activation, and PARP cleavage and altered mitochondrial membrane potential and release of cytochrome c and apoptosis-inducing factor and phosphorylation and subsequent activation of p38-MAPK, stress-activated kinases (SAPK/JNK), protein kinase C, and cytoplasmic phospholipase A2 in RAW cells. Further, phosphorylation and degradation of inhibitory kappaB and consequent activation and nuclear translocation of the redox-sensitive transcription factor NF-kappaB were significantly prevented by benfotiamine. The LPS-induced increased expression of cytokines and chemokines and the inflammatory marker proteins iNOS and COX-2 and their metabolic products NO and PGE(2) was also blocked significantly. Thus, our results elucidate the molecular mechanism of the anti-inflammatory action of benfotiamine in LPS-induced inflammation in murine macrophages. Benfotiamine suppresses oxidative stress-induced NF-kappaB activation and prevents bacterial endotoxin-induced inflammation, indicating that vitamin B1 supplementation could be beneficial in the treatment of inflammatory diseases.
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Citotoxicidad Inmunológica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Tiamina/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Factor Inductor de la Apoptosis/biosíntesis , Factor Inductor de la Apoptosis/genética , Factor Inductor de la Apoptosis/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Citocromos c/biosíntesis , Citocromos c/genética , Citocromos c/metabolismo , Citoprotección , Activación Enzimática/efectos de los fármacos , Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Activación de Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Tiamina/farmacologíaRESUMEN
PURPOSE: To investigate the genotoxic effects of lutein (LBP) and beta -carotene breakdown products (beta -apo-8-carotenal, BA8C) and the preventive role of GSH in human retinal pigment epithelial cells (ARPE-19). METHODS: LBP- and BA8C-induced DNA damage in human retinal pigment epithelial cells (ARPE-19) was determined by comet assay. The DNA damage was quantified by the image analysis system using Comet Score software. ARPE-19 cell viability was determined by CellTiter 96 AQ(ueous) one-solution cell proliferation assay kit. Intracellular GSH levels were measured by Ellman's reagent. RESULTS: Incubation of serum-starved ARPE-19 cells with LBP and BA8C caused significant DNA damage in a dose- and time-dependent manner. The DNA damage and cell death incurred by LBP and BA8C were significantly prevented by N-acetylcysteine (NAC) but not by alpha -tocopherol + ascorbic acid (T + AA). Furthermore, BSO-induced GSH depletion in ARPE-19 cells caused a significant elevation in LBP- and BA8C-induced DNA damage, whereas increased GSH levels in ARPE-19 cells prevented it. CONCLUSIONS: Our results suggest that breakdown products of dietary carotenoids could be genotoxic in ARPE-19 cells. LBP-induced genotoxic effects could worsen oxidative stress. The intracellular GSH pool in ARPE-19 cells might play a critical role in carotenoid breakdown products-induced genotoxicity.
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Carotenoides/toxicidad , Daño del ADN , ADN/efectos de los fármacos , Luteína/toxicidad , Epitelio Pigmentado de la Retina/efectos de los fármacos , Acetilcisteína/farmacología , Apoptosis/efectos de los fármacos , Ácido Ascórbico/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Glutatión/farmacología , Humanos , Microscopía Fluorescente , Factores de Tiempo , alfa-Tocoferol/farmacologíaRESUMEN
Cadmium (Cd), released from cigarette smoke and metal industrial activities, is known to accumulate in human body organs including retina and is particularly higher in retinal tissues of age-related macular degeneration (AMD) eyes compared to non-AMD eyes. We have determined the cytotoxic effects of Cd on human retinal pigment epithelial (RPE) cells. Upon Cd treatment, there was a dose- and time-dependent decline in ARPE-19 cell viability as well as early apoptotic changes such as altered mitochondrial membrane potential (MMP) and Cytochrome C release in cytosol. Depletion of GSH by buthionine-[S,R]-sulfoximine (BSO) resulted in increased Cd toxicity in ARPE-19 cells. Cadmium also caused reactive oxygen species (ROS) generation and activation of mitogen-activated protein kinases (MAPKs) pathway including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (Erk1/2), and p38 in ARPE-19 cells. Antioxidants such as N-acetylcysteine (NAC) significantly reduced Cd-induced toxicity. These results indicate that elevated ROS-induced activation of the MAPK signaling pathway could be associated with Cd-induced RPE cell apoptosis, one of the major contributing factors in AMD. The toxic effects of Cd on ARPE-19 cells indicate that environmental heavy metals such as Cd could be important potential factors in RPE cells death associated retinal diseases particularly related to smoking.
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Apoptosis/efectos de los fármacos , Cloruro de Cadmio/toxicidad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Epitelio Pigmentado de la Retina/patología , Acetilcisteína/farmacología , Western Blotting , Butionina Sulfoximina/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Citosol/enzimología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Glutatión/metabolismo , Humanos , Peróxido de Hidrógeno/toxicidad , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Factores de TiempoRESUMEN
Carotenoids have been advocated as potential therapeutic agents in treating age-related macular degeneration (AMD). In ocular tissues carotenoids may undergo oxidation and form carotenoid-derived aldehydes (CDA), which would be toxic to tissues. We have investigated the cytotoxic effects of CDA from beta-carotene, Lutein and Zeaxanthin on human retinal pigment epithelial cells (ARPE-19). The serum-starved ARPE-19 cells were treated with CDA without or with antioxidant, N-acetylcysteine (NAC) and cell viability, apoptosis, reactive oxygen species (ROS) levels, nuclear chromatin condensation as well as fragmentation, change in mitochondrial membrane potential (MMP) and activation of transcription factors NF-kappaB and AP-1 were determined. We observed a dose and time-dependent decline in cell viability upon incubation of ARPE-19 cells with CDA. The CDA treatment also led to elevation in ROS levels in a dose-dependent manner. Upon CDA treatment a significant number of apoptotic cells were observed. Also early apoptotic changes in ARPE-19 cells induced by CDA were associated with change in MMP. Increased nuclear chromatin condensation and fragmentation were also observed in cells treated with CDA. The cytotoxicity of CDA in ARPE-19 cells was significantly ameliorated by the antioxidant, NAC. Furthermore, CDA induced the activation of NF-kappaB and AP-1 which was significantly inhibited by NAC. Thus our results demonstrate that CDA could increase the oxidative stress in ARPE-19 cells by elevating ROS levels that would cause imbalance in cellular redox status, which could lead to cell death. This would suggest that high carotenoid supplementation for treatment of AMD should be used cautiously.