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PURPOSE: The causes of epidural catheter migration beneath the skin have not been previously investigated. We hypothesized that greater subcutaneous fat thickness might be associated with increased catheter migration beneath the skin. METHODS: We conducted a retrospective cross-sectional study of patients who had undergone combined general and epidural anesthesia, selecting individuals who received thoracic and abdominal CT scans within the first 5 postoperative days. Needle depth was defined as the distance from the needle tip to the skin surface when the anesthesiologist determined that the needle tip had reached the epidural space. We measured the length of the epidural catheter from the skin surface to the epidural space (catheter length), and subcutaneous fat thickness (fat thickness) using CT imaging. Migration distance was calculated by subtracting needle depth from catheter length. RESULTS: We analyzed 127 patients (72 males), all undergoing epidural catheter insertion in the left lateral decubitus position via a paramedian approach. The median age of the patients was 71 years. Epidural catheters were postoperatively found to substantially curve beneath the skin. Regression analysis revealed no significant influence of fat thickness on catheter length (regression coefficient 0.10, 95% confidence interval [CI]: - 0.17, 0.38). However, it indicated a positive correlation between fat thickness and needle depth (regression coefficient 0.50, 95% CI: 0.30, 0.70), and a negative correlation between fat thickness and migration distance (regression coefficient - 0.40, 95% CI: - 0.65, - 0.14). CONCLUSION: We found a negative correlation between epidural catheter migration beneath the skin and subcutaneous fat thickness. Anesthesiologists should be aware of the possibility of substantial subcutaneous curving of the catheter, especially in patients with scant subcutaneous fat.
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Ricin toxin A chain (RTA), from Ricinus communis, is a deadly protein that inactivates ribosomes by degrading an adenine residue at position 4324 in 28S rRNA. Recently, we have demonstrated that pterin-7-carboxamides with peptide pendants were potent RTA inhibitors. Among these, N-(pterin-7-carbonyl)glycyl-L-tyrosine (7PCGY) is the most potent RTA inhibitor as a small organic molecule. However, despite this fascinating inhibitory activity, the mode of interaction of 7PCGY with RTA remains elusive. This study aimed to elucidate the factors responsible for the high RTA inhibitory activity of 7PCGY based on X-ray crystallographic analysis. Herein, we report the successfully resolved X-ray crystal structure of 7PCGY/RTA complexes, revealing that the interaction between the phenolic hydroxy group in 7PCGY and Asn78 of RTA through a hydrogen bonding and the conformational change of Tyr80 and Asn122 are responsible for the high RTA inhibitory activity of 7PCGY.
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Ricina , Ricina/química , Ricina/genética , Ricina/metabolismo , Pterinas/química , Pterinas/farmacología , Cristalografía por Rayos X , PéptidosRESUMEN
Foxp3+ regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear. In this study, we used Foxp3 conditional knockout mice to conditionally ablate the Foxp3 gene in adult mice and examine the relationship between Treg cells and intestinal bacterial communities. Deletion of Foxp3 reduced the relative abundance of Clostridia, suggesting that Treg cells have a role in maintaining Treg-inducing microbes. Additionally, the knockout increased the levels of fecal immunoglobulins and immunoglobulin-coated bacteria. This increase was due to immunoglobulin leakage into the gut lumen as a result of loss of mucosal integrity, which is dependent on the gut microbiota. Our findings suggest that Treg cell dysfunction leads to gut dysbiosis via aberrant antibody binding to the intestinal microbes.
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Microbioma Gastrointestinal , Linfocitos T Reguladores , Ratones , Animales , Disbiosis/metabolismo , Intestinos/microbiología , Bacterias/metabolismo , Ratones Noqueados , Inmunoglobulina A/metabolismo , Factores de Transcripción Forkhead/genéticaRESUMEN
The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease. The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation. The role of the lectin pathway (LP) in lupus has remained largely unknown. Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP. MASP-1 encoded by the Masp1 gene significantly contributes to the activation of the LP. After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the Masp1 gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb. To investigate the roles of MASP-1 and MASP-3 in lupus, we generated Masp1 gene knockout lupus-prone MRL/lpr mice (Masp1/3-/- MRL/lpr mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease. As expected, sera from Masp1/3-/- MRL/lpr mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD. Compared to their wild-type littermates, the Masp1/3-/- MRL/lpr mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score. On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and Masp1/3-/- MRL/lpr mice. Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/lpr mice, most likely via activation of the LP and/or AP.
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Vía Alternativa del Complemento/inmunología , Lectina de Unión a Manosa de la Vía del Complemento/inmunología , Nefritis Lúpica/inmunología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/inmunología , Animales , Convertasas de Complemento C3-C5/genética , Convertasas de Complemento C3-C5/inmunología , Vía Alternativa del Complemento/genética , Lectina de Unión a Manosa de la Vía del Complemento/genética , Nefritis Lúpica/genética , Nefritis Lúpica/patología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Ratones , Ratones Endogámicos MRL lpr , Ratones NoqueadosRESUMEN
BACKGROUND: The objective of this study was to determine the required concentration of egg white (EW) in the diet to induce oral desensitization and/or immune tolerance within 4 weeks of oral immunotherapy (OIT) in an EW allergic mouse model. METHODS: Female BALB/c mice were systemically sensitized to EW by intraperitoneal injections and subsequently subjected to oral allergen gavage. Sensitized mice were provided 4 weeks of OIT by supplementing with 0 (non-OIT), 0.01, 0.1, or 1% EW in a 20% casein diet. Nonsensitized mice served as the nonallergy group. We performed oral and intraperitoneal EW challenges, assessed vascular permeability in the dorsal skin, and measured allergic biomarkers. RESULTS: The change in rectal temperature after oral challenge was not significantly different between the nonallergy and 1% EW groups, and the frequency of diarrhea in the 1% EW group was lower than that in the non-OIT group. The levels of plasma ovomucoid-specific IgE, IgA, and IgG2a in the 1% EW group at the study endpoint were significantly lower than those in the non-OIT group. IFN-γ and IL-10 secretions of spleen lymphocytes in the 1% EW group were significantly higher than those in the non-OIT group, and the percentage of CD4+Foxp3+ cells in the 1% EW group was higher than that in the non-OIT group. CONCLUSION: These results suggested that diet supplemented with 1% EW can induce oral desensitization and immune tolerance in the EW allergic mouse model.
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Desensibilización Inmunológica , Hipersensibilidad al Huevo/terapia , Clara de Huevo/efectos adversos , Tolerancia Inmunológica , Animales , Diferenciación Celular , Citocinas/sangre , Suplementos Dietéticos , Modelos Animales de Enfermedad , Hipersensibilidad al Huevo/inmunología , Femenino , Inmunoglobulinas/sangre , Ratones , Ratones Endogámicos BALB C , Ovomucina/inmunologíaRESUMEN
Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles.
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Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Carcinogénesis/genética , Mieloma Múltiple/genética , Transducción de Señal/genética , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/antagonistas & inhibidores , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mieloma Múltiple/patologíaRESUMEN
The pathogenetic roles of 8q24 amplified segments in leukemic cells with double minute chromosomes remain to be verified. Through comprehensive molecular analyses of 8q24 amplicons in leukemic cells from an acute myelogenous leukemia (AML) patient and AML-derived cell line HL60 cells, we identified two novel fusion genes between NSMCE2 and long noncoding RNAs (lncRNAs), namely, PVT1-NSMCE2 and BF104016-NSMCE2. Our study suggests that 8q24 amplicons are associated with the emergence of aberrant chimeric genes between NSMCE2 and oncogenic lncRNAs, and also implicate that the chimeric genes involving lncRNAs potentially possess as-yet-unknown oncogenic functional roles.
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Cromosomas Humanos Par 8/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mieloide Aguda/genética , Ligasas/genética , ARN Largo no Codificante/genética , Cariotipo Anormal , Anciano , Femenino , Amplificación de Genes , Células HL-60 , Humanos , CariotipificaciónRESUMEN
This report concerns a 62-year-old man with primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type that developed during methotrexate (MTX) treatment for rheumatoid arthritis (RA). Several tumors were observed on the left lower leg. A histological analysis showed diffuse proliferation of large neoplastic B-cells that were immunophenotypically CD10-/MUM1+/BCL6-/BCL2+ and cytogenetically had IgH/c-MYC translocation without translocation involving BCL6 or IgH/BCL2. No evidence of Epstein-Barr virus (EBV) infection was found. The discontinuation of MTX resulted in a 20-month disease-free period. No previous cases of PCLBCL, leg type associated with RA or MTX therapy have been reported. The phenotypes of our patient were partly different from those of typical PCLBCL, leg type or RA/MTX-associated lymphoma.
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Artritis Reumatoide/complicaciones , Linfoma de Células B/etiología , Metotrexato/efectos adversos , Anciano , Artritis Reumatoide/tratamiento farmacológico , Linfocitos B , Humanos , Pierna/patología , Linfoma de Células B/genética , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Translocación GenéticaRESUMEN
The monocytic leukemia zinc finger protein KAT6A (formerly MOZ) gene is recurrently rearranged by chromosomal translocations in acute myeloid leukemia (AML). KAT6A is known to be fused to several genes, all of which have histone acetyltransferase (HAT) activity and interact with a number of transcription factors as a transcriptional coactivator. The present study shows that the leucine twenty homeobox (LEUTX) gene on 19q13 is fused to the KAT6A gene on 8p11 in a therapy-related AML with t(8;19)(p11;q13) using the cDNA bubble PCR method. The fusion transcripts contained 83 nucleotides upstream of the first ATG of LEUTX and are presumed to create in-frame fusion proteins. LEUTX is known to have a homeobox domain. Expression of the LEUTX gene was only detected in placenta RNA by RT-PCR, but not in any tissues by Northern blot analysis. The putative LEUTX protein does not contain any HAT domain, and this is the first study to report that KAT6A can fuse to the homeobox gene. The current study, with identification of a new partner gene to KAT6A in a therapy-related AML, does not elucidate the mechanisms of leukemogenesis in KAT6A-related AML but describes a new gene with a different putative function.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cromosomas Humanos Par 19/genética , Cromosomas Humanos Par 8/genética , Histona Acetiltransferasas/genética , Proteínas de Homeodominio/genética , Leucemia Mieloide Aguda/genética , Secuencia de Aminoácidos , Secuencia de Bases , Resultado Fatal , Fusión Génica , Genes Homeobox , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Datos de Secuencia Molecular , Translocación GenéticaRESUMEN
AIM: To assess the prevalence of autoantibodies against nucleosomes (anti-nucleosome Ab) in patients with autoimmune hepatitis (AIH), examine the correlation between anti-nucleosome Ab and disease activity, and evaluate the effectiveness of anti-nucleosome Ab in predicting relapse. METHODS: We analyzed serum anti-nucleosome Ab levels in 38 patients with AIH by enzyme-linked immunosorbent assay, and assessed their correlation with clinical characteristics. RESULTS: Anti-nucleosome Ab levels were significantly higher in AIH, but not in patients with chronic hepatitis B (n = 20) or chronic hepatitis C (n = 20), compared to healthy controls (n = 15). The positive prevalence of anti-nucleosome Ab was 71.1% in AIH. Anti-nucleosome Ab levels were significantly lower during remission compared to that during flares within the same patients with AIH. Total bilirubin levels were significantly higher in patients with anti-nucleosome Ab levels of 53.7 U/mL or more compared to those with less than 53.7 U/mL at disease onset. Analysis of the reduction in anti-nucleosome Ab by immunosuppressive therapy in 16 AIH patients revealed that age at disease onset was significantly lower and IgG levels and relapse rates were significantly higher in patients with a reduction rate of less than 35% compared to those with a reduction rate 35% or more. The International Autoimmune Hepatitis Group score and γ-globulin levels were also higher in patients with reduction rates of less than 35% (borderline significance). CONCLUSION: Anti-nucleosome Ab in AIH patients may be useful markers not only for disease diagnosis, but also for activity assessment and relapse prediction.
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AIM: The aim of this study was to clarify the relationship between the expression of micro-RNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) and clinical presentation in patients with primary biliary cirrhosis (PBC). METHODS: This study involved 58 patients with PBC, patients with control diseases including 25 patients with autoimmune hepatitis (AIH), six patients with PBC-AIH overlap syndrome, 23 patients with systemic lupus erythematosus (SLE), and 30 healthy controls. After miRNA was extracted from PBMCs, the expressions of miR-26a, miR-328, miR-299-5p, miR-146a, miR-155, miR-16, miR-132 and let7a were quantified by real-time PCR. The relationships between all miRNA expressions and clinical test parameters were also examined. RESULTS: In PBC, the expressions of miR-155 and miR-146a were significantly increased compared to those in healthy controls. For miR-26a, miR-299-5p, miR-328 and let-7a, although no significant difference was observed in expression between patients and healthy controls, expressions were significantly increased in PBC compared to those in AIH. Expressions of miR-299-5p were significantly increased in PBC patients resistant to treatment with ursodeoxycholic acid (n = 18) compared to those in healthy controls. In the evaluation of the relationship between miRNA expression and clinical test parameters, significant and positive correlations were found for miR-299-5p with alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin and immunoglobulin M levels. CONCLUSION: The preset results suggest the existence of miRNAs that exhibit disease-specific increases in expression and miRNAs closely correlated with clinical test values in PBC. Further analyses of these miRNAs may contribute to the elucidation of the pathology of PBC.
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PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia (CML), however, the cell killing mechanism underlying its anti-leukemic activity has remained to be verified. We investigated the precise mechanisms underlying the apoptosis induction by FTY720, especially focusing on the roles of BH3-only proteins, and the therapeutic potency of FTY720 for CML. Enforced expression of either BCL2 or the dominant-negative protein of FADD (FADD.DN) partly protected CML cells from apoptosis by FTY720, indicating the involvement of both cell extrinsic and intrinsic apoptosis pathways. FTY720 activates pro-apoptotic BH3-only proteins: BIM, which is essential for apoptosis by BCR-ABL1 tyrosine kinase inhibitors (TKIs), and BID, which accelerates the extrinsic apoptosis pathway. Gene knockdown of either BIM or BID partly protected K562 cells from apoptosis by FTY720, but the extent of cell protection was not as much as that by overexpression of either BCL2 or FADD.DN. Moreover, knockdown of both BIM and BID did not provide additional protection compared with knockdown of only BIM or BID, indicating that BIM and BID complement each other in apoptosis by FTY720, especially when either is functionally impaired. FTY720 can overcome TKI resistance caused by ABL kinase domain mutations, dysfunction of BIM resulting from gene deletion polymorphism, and galectin-3 overexpression. In addition, ABT-263, a BH3-mimetic, significantly augmented cell death induction by FTY720 both in TKI-sensitive and -resistant leukemic cells. These results provide the rationale that FTY720, with its unique effects on BIM and BID, could lead to new therapeutic strategies for CML.
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Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas de la Membrana/genética , Glicoles de Propileno/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Esfingosina/análogos & derivados , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/antagonistas & inhibidores , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Proteína 11 Similar a Bcl2 , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Clorhidrato de Fingolimod , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Mutación , Cultivo Primario de Células , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Esfingosina/farmacología , Proteína Letal Asociada a bcl/genética , Proteína Letal Asociada a bcl/metabolismoAsunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 8 , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Eliminación de Gen , Linfoma de Células B/genética , Proteínas/genética , Humanos , Linfoma de Células B/patología , ARN Largo no CodificanteRESUMEN
Bacterial infection (i.e., Streptococcus sanguinis) has been suggested to be related to pathogenesis and/or symptom of Behcet's disease (BD). Toll-like receptor 9 (TLR9) plays an important role in both the innate and adaptive immune systems by recognizing a component of bacterial DNA (i.e., CpG-DNA). Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) in TLR9 were associated with infectious and autoimmune/autoinflammatory diseases. In this study, we detected five SNPs with BD patients in a Japanese population. Allele frequency analysis of the three common SNPs (-1486: T/C (promoter region), 1174: A/G (intron 1), 2848: G/A (exon 2; Pro545Pro)) showed no statistically significant difference between the BD patients and the healthy controls. However, genotyping analysis revealed that the homozygous genotypes -1486CC and 1174GG were significantly more frequent in the BD patients compared to the healthy controls (P = 0.048 and P = 0.027, respectively). The homozygous diplotype distribution C-G-A/C-G-A was significantly more frequent in the BD patients compared to the healthy controls (P = 0.041). For reporter gene assay, the plasmid construct carrying diplotype distribution C-G/C-G of the -1486T/C and 1174A/G SNPs showed significantly higher luciferase activity compared to the plasmid construct carrying diplotype distribution T-A/T-A (P = 0.019). These results suggested an association of the homozygous genotypes and homozygous diplotype configuration of the TLR9 SNPs with susceptibility to BD in the Japanese population.
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Síndrome de Behçet/genética , Receptor Toll-Like 9/genética , Adulto , Anciano , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Pueblo Asiatico/genética , Síndrome de Behçet/inmunología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Japón , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2(Ser227), which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma-derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2(Ser227) by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21(WAF1/CIP1), and MCL1. RSK2(Ser227) inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6-mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLX(L) inhibitors. These results suggest that RSK2(Ser227) is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies.
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Mieloma Múltiple/enzimología , Mieloma Múltiple/terapia , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/genética , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Humanos , Terapia Molecular Dirigida , Mieloma Múltiple/genética , Fosforilación , Dominios y Motivos de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Pteridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Transducción de Señal , TransfecciónRESUMEN
OBJECTIVE: The incorporation of rituximab in immunochemotherapy has improved treatment outcomes for diffuse large B-cell lymphoma, but the prognosis for some diffuse large B-cell lymphomas remains dismal. Identification of adverse prognostic subgroups is essential for the choice of appropriate therapeutic strategy. METHODS: We retrospectively investigated the impact of so-called 'double-hit' cytogenetic abnormalities, i.e. cytogenetic abnormalities involving c-MYC co-existing with other poor prognostic cytogenetic abnormalities involving BCL2, BCL6 or BACH2, on treatment outcomes for 93 consecutive diffuse large B-cell lymphoma patients. RESULTS: According to the revised international prognostic index, no patients were cytogenetically diagnosed with double-hit lymphomas in the 'very good' risk group or in the 'good' risk group, while 5 of 33 patients had double-hit lymphomas in the 'poor' risk group. All the double-hit lymphoma patients possessed both nodal and extranodal involvement. The overall complete response rate was 89.3%, overall survival 87.1% and progression-free survival 75.8% over 2 years (median observation period: 644 days). The complete response rates were 93.2% for the non-double-hit lymphoma patients and 40.0% for the double-hit lymphoma patients. Significantly longer progression-free survival and overall survival were observed for the 'very good' and the 'good' risk patients than for the 'poor' risk patients. Moreover, the progression-free survival of double-hit lymphoma was significantly shorter than that of the non-double-hit lymphoma 'poor' risk patients (P = 0.016). In addition, the overall survival of the double-hit lymphoma patients also tended to be shorter than that of the non-double-hit lymphoma 'poor' risk group. CONCLUSIONS: The diagnosis of double-hit lymphoma can help discriminate a subgroup of highly aggressive diffuse large B-cell lymphomas and indicate the need for the development of novel therapeutic strategies for double-hit lymphoma.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Aberraciones Cromosómicas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Genes myc/genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Estudios Retrospectivos , Rituximab , Resultado del TratamientoRESUMEN
AIMS: Plasmablastic lymphoma (PBL) is an aggressive lymphoma with a terminally differentiated B cell phenotype; half of patients with this disease have Epstein-Barr virus (EBV) infection. The majority of PBL cases are associated with human immunodeficiency virus (HIV) infection, while the remaining HIV-negative cases were accompanied by other immunodeficiency conditions or immunosenescence in the elderly. METHODS AND RESULTS: To characterize HIV-negative PBL of the elderly (PBL-E), we compared the clinicopathological characteristics of 10 cases of PBL-E and 124 cases with age-related EBV-associated B cell lymphoproliferative disorder (AR-EBVLPD). The 10 PBL-E (eight men, two women; median age: 68 years) were associated with a more indolent clinical behaviour and a better overall survival than AR-EBVLPD. Extranodal involvement was higher in PBL-E (50%) than AR-EBVLPD; notably, the nasal cavity was affected most frequently in PBL-E (60%). Immunoglobulin heavy chain/(IGH)/MYC translocation was detected in half of the PBL-E cases. CONCLUSIONS: PBL-E shares some clinical features with AR-EBVLPD, such as HIV negativity, old age, and EBV infection, no known immunosuppressive condition but there are some differences such as a higher ratio of extranodal involvement and better prognosis. PBL-E is a newly recognized condition and should be distinguished from HIV-positive PBL, sharing features with AR-EBVLPD in particular, immunosenescence of the elderly.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Linfoma de Células B/patología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Trastornos Linfoproliferativos/genética , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética/genéticaRESUMEN
Chromosome 8q24 rearrangements are occasionally found in multiple myeloma and are associated with tumor progression. The 8q24 rearrangements were detected by FISH in 12 of 54 patients with multiple myeloma (22.2%) and in 8 of 11 multiple myeloma cell lines (72.7%). The breakpoints of 8q24 in 10 patients with multiple myeloma and in all multiple myeloma cell lines were assigned to a 360 kb segment, which was divided into 4 regions: approximately 120 kb centromeric to MYC (5' side of MYC), the region centromerically adjacent to PVT1 (~ 170 kb region, including MYC, of 5' side of PVT1), the PVT1 region, and the telomeric region to PVT1. PVT1 rearrangements were most common and found in 7 of 12 patients (58.3%) and 5 of 8 cell lines (62.5%) with 8q24 abnormalities. A combination of spectral karyotyping (SKY), FISH, and oligonucleotide array identified several partner loci of PVT1 rearrangements, such as 4p16, 4q13, 13q13, 14q32, and 16q23-24. Two novel chimeric genes were identified: PVT1-NBEA in the AMU-MM1 cell line harboring t(8;13)(q24;q13) and PVT1-WWOX in RPMI8226 cell line harboring der(16)t(16;22)ins(16;8)(q23;q24). The PVT1-NBEA chimera in which PVT1 exon 1 was fused to NBEA exon 2 and the PVT1-WWOX in which PVT1 exon 1 was fused to WWOX exon 9 were associated with the expression of abnormal NBEA and WWOX lacking their N-terminus, respectively. These findings suggest that PVT1 rearrangements may represent a novel molecular paradigm underlying the pathology of 8q24 rearrangement-positive multiple myeloma.
Asunto(s)
Cromosomas Humanos Par 8/genética , Mieloma Múltiple/genética , Proteínas de Fusión Oncogénica/genética , Proteínas/genética , Proteínas Portadoras/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 4/genética , Regulación Neoplásica de la Expresión Génica , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Análisis por Micromatrices/métodos , Mieloma Múltiple/patología , Proteínas del Tejido Nervioso/genética , Oxidorreductasas/genética , Polimorfismo de Nucleótido Simple , Interferencia de ARN , ARN Largo no Codificante , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cariotipificación Espectral , Proteínas Supresoras de Tumor/genética , Oxidorreductasa que Contiene Dominios WWRESUMEN
We retrospectively investigated the prognostic impact of high-risk cytogenetic abnormalities (CAs) on the outcome of treatment with bortezomib plus dexamethasone (BD) in 43 relapsed/refractory (Rel/Ref) multiple myeloma patients. Fluorescence in situ hybridization (FISH) analysis identified del(13q) in 25 patients, t(4;14) in 14, t(14;16) in 4, 1q21 abnormality in 12 and del(17p) in 2, while G-banding also detected chromosome 13 monosomy (-13) in metaphase spreads from 7 patients. Eighteen of 25 patients with FISH-detected chromosome 13 abnormalities also exhibited other abnormalities. Median observation period was 510 days, and median overall survival (OS) and progression-free survival (PFS) were 912 days and 162 days, respectively. Detection of del(13q), t(4;14), t(14;16) or 1q21 abnormalities by FISH and co-occurrence of chromosome 13 abnormality with other abnormalities were not associated with poorer outcomes. In contrast, detection of -13 by G-banding in metaphase spreads showed significant association with shorter OS, although the overall response rate and PFS were not inferior to those for patients without -13 detected by G-banding. BD therapy may be a potent weapon for overcoming most classical high-risk CAs, while the detection of -13 in metaphase spreads may serve as a predictor of highly progressive disease, even when treated with BD.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 13/genética , Dexametasona/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Pirazinas/uso terapéutico , Adulto , Anciano , Bortezomib , Aberraciones Cromosómicas , Femenino , Humanos , Masculino , Metafase , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Pronóstico , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
In this study, we established and analyzed a novel human myeloid leukemia cell line, AMU-AML1, from a patient with acute myeloid leukemia with multilineage dysplasia before the initiation of chemotherapy. AMU-AML1 cells were positive for CD13, CD33, CD117, and HLA-DR by flow cytometry analysis and showed a single chromosomal abnormality, 46, XY, t(12;22)(p13;q11.2), by G-banding and spectral karyotyping. Fluorescent in situ hybridization analysis indicated that the chromosomal breakpoint in band 12p13 was in the sequence from the 5' untranslated region to intron 1 of TEL and that the chromosomal breakpoint in band 22q11 was in the 3' untranslated region of MN1. The chimeric transcript and protein of MN1-TEL could not be detected by reverse-transcriptase polymerase chain reaction or Western blot analysis. However, the MN1 gene was amplified to three copies detected by array comparative genomic hybridization analysis, and the expression levels of the MN1 transcript and protein were high in AMU-AML1 cells when compared with other cell lines with t(12;22)(p13;q11-12). Our data showed that AMU-AML1 cells contain t(12;22)(p13;q11.2) without chimeric fusion of MN1 and TEL. The AMU-AML1 cells gained MN1 copies and had high expression levels of MN1. Thus, the AMU-AML1 cell line is useful for studying the biological consequences of t(12;22)(p13;q11.2) lacking chimeric MN1-TEL.