RESUMO
Diffuse Large B-cell Lymphoma (DLBCL), with its intrinsic genetic and epigenetic heterogeneity, exhibits significantly variable clinical outcomes among patients treated with the current standard regimen. Disulfidptosis, a novel form of regulatory cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to intracellular accumulation of disulfides. We investigated the expression variations of disulfidptosis-related genes (DRGs) in DLBCL using two publicly available gene expression datasets. The initial analysis of DRGs in DLBCL (GSE12453) revealed differences in gene expression patterns between various normal B cells and DLBCL. Subsequent analysis (GSE31312) identified DRGs strongly associated with prognostic outcomes, revealing eight characteristic DRGs (CAPZB, DSTN, GYS1, IQGAP1, MYH9, NDUFA11, NDUFS1, OXSM). Based on these DRGs, DLBCL patients were stratified into three groups, indicating that (1) DRGs can predict prognosis, and (2) DRGs can help identify novel therapeutic candidates. This study underscores the significant role of DRGs in various biological processes within DLBCL. Assessing the risk scores of individual DRGs allows for more precise stratification of prognosis and treatment strategies for DLBCL patients, thereby enhancing the effectiveness of clinical practice.
Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Humanos , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão GênicaRESUMO
BACKGROUND: The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor. METHODS: Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group. CONCLUSIONS: Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .).
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Fatores Imunológicos/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Infecções/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Neutropenia/induzido quimicamente , Talidomida/administração & dosagem , Talidomida/efeitos adversosRESUMO
We assessed the efficacy and safety of weekly cyclophosphamide-bortezomib-dexamethasone (CBD) induction prior to autologous stem cell transplantation (ASCT) in newly diagnosed Japanese patients with multiple myeloma (MM). This regimen consisted of four 28-day cycles of once-weekly oral cyclophosphamide (300 mg/m2), subcutaneous bortezomib (1.3 mg/m2), and oral dexamethasone (40 mg). Responding patients underwent stem cell collection followed by ASCT. The primary endpoint was the postinduction rate of achieving a near complete response (nCR) or better. Among the 38 enrolled patients, a complete response (CR), an nCR, a very good partial response (VGPR), and a partial response (PR) were achieved in 10.5, 2.6, 23.7, and 36.8% of cases, respectively. A grade 4 hematological adverse event (AE) was observed in 1 patient. Grade 3-4 infection, including febrile neutropenia, was observed in 4 patients (10.5%). Although 2 patients dropped out due to AE, 94.7% of the patients completed the induction phase. However, because of a poor response to induction chemotherapy (Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Bortezomib/administração & dosagem
, Ciclofosfamida/administração & dosagem
, Dexametasona/administração & dosagem
, Mieloma Múltiplo/tratamento farmacológico
, Adolescente
, Adulto
, Idoso
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Bortezomib/efeitos adversos
, Ciclofosfamida/efeitos adversos
, Dexametasona/efeitos adversos
, Esquema de Medicação
, Feminino
, Doenças Hematológicas/etiologia
, Transplante de Células-Tronco Hematopoéticas
, Humanos
, Japão
, Masculino
, Pessoa de Meia-Idade
, Mieloma Múltiplo/diagnóstico
, Mieloma Múltiplo/mortalidade
, Análise de Sobrevida
, Transplante Autólogo
, Resultado do Tratamento
, Adulto Jovem
RESUMO
AIMS: To explore the biomarker for predicting the occurrence of adverse events in myeloma patients treated by intravenous bortezomib, we measured proteasome activity in peripheral blood mononuclear cells. METHODS: Samples were obtained from 34 bortezomib-naïve patients. Proteasome activity was measured at pre- and postchemotherapy phase by using a synthetic substrate. RESULTS: Bortezomib injection resulted in a dramatic decrease in proteasome activity, reaching 32.4 ± 18.79% (mean ± SD) of the pretreatment level at 1 h, but it generally recovered at the end of the first course. In total, 6 patients manifested with severe bortezomib-induced peripheral neuropathy (sBIPN) in the second-third course. There was a nonsignificant trend for these patients to have lower levels of the relative proteasome activity at the end of the first course than those without sBIPN (median: 74.03 vs. 103.2%, p = 0.052). Moreover, in all of them, proteasome activity did not recover to the pretreatment level, whereas no patients with complete recovery manifested with sBIPN. Analysis with Fisher's exact test demonstrated that incomplete recovery of proteasome activity is a significant risk factor for sBIPN (p = 0.014). CONCLUSION: Patients with incomplete recovery of proteasome activity are at high risk for developing sBIPN, and the susceptible patients can be indicated by monitoring proteasome activity.
Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Leucócitos Mononucleares , Mieloma Múltiplo , Proteínas de Neoplasias/metabolismo , Doenças do Sistema Nervoso Periférico , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Ácidos Borônicos/administração & dosagem , Bortezomib , Suscetibilidade a Doenças , Feminino , Seguimentos , Humanos , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/enzimologia , Doenças do Sistema Nervoso Periférico/patologia , Pirazinas/administração & dosagemRESUMO
PURPOSE: In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results. METHODS: Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically. RESULTS: A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected. CONCLUSION: EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Análise de Sobrevida , DexametasonaRESUMO
Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.
RESUMO
Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms. B lymphomas occurring in Fasl mutant (gld) mice usually are immunoglobulin (Ig) isotype switched, secrete Ig, and are plasmacytoid in appearance but lack Myc translocations characteristic of other plasma cell (PC) neoplasms. Here, we explore the relationship between B cell autoreactivity and transformation and use gene expression profiling to further classify gld plasmacytoid lymphomas (PLs) and to identify genes of potential importance in transformation. We found that the majority of PLs derive from antigen-experienced autoreactive B cells producing antinuclear antibody or rheumatoid factor and exhibit the skewed Ig V gene repertoire and Ig gene rearrangement patterns associated with these specificities. Gene expression profiling revealed that both primary and transplanted PLs share a transcriptional profile that places them at an early stage in PC differentiation and distinguishes them from other B cell neoplasms. In addition, genes were identified whose altered expression might be relevant in lymphomagenesis. Our findings provide a strong case for targeted transformation of autoreactive B cells in gld mice and establish a valuable model for understanding the relationship between systemic autoimmunity and B cell neoplasia.
Assuntos
Autoimunidade , Transformação Celular Neoplásica , Linfoma de Células B/etiologia , Glicoproteínas de Membrana/fisiologia , Plasmócitos/patologia , Animais , Especificidade de Anticorpos , Linfócitos B/imunologia , Proteína Ligante Fas , Perfilação da Expressão Gênica , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma de Células B/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3HRESUMO
Novel therapies are needed for patients with newly diagnosed multiple myeloma (NDMM). Elotuzumab plus lenalidomide and dexamethasone (ELd) is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2 study in Japan evaluated ELd vs lenalidomide and dexamethasone (Ld) in patients with NDMM who were ineligible for stem cell transplantation. Elotuzumab infusion was accelerated to 5 mL/min by dose 3, cycle 1, allowing most subsequent infusions to be completed within 1 h. The primary endpoint was overall response rate (ORR) in the ELd arm. Secondary endpoints were the difference in ORR between treatments, and progression-free survival (PFS). Patients were randomized to ELd (n = 40) or Ld (n = 42); median number of treatment cycles was 13 (ELd) and 12 (Ld). In the ELd arm, ORR was 88% [70% confidence interval (CI) 80-93]. The estimated difference in ORR between treatments was 13% (95% CI - 4, 30) in favor of ELd. Progression-free survival data were immature. Safety was consistent with previous findings of ELd in Japanese patients with RRMM. No infusion reactions occurred at the maximum rate of 5 mL/min, which was used in 89% of elotuzumab infusions. ELd may be an effective, well-tolerated frontline treatment for patients with NDMM ineligible for stem cell transplantation.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Japão , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Intervalo Livre de Progressão , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
SLAMF7 is expressed mainly on multiple myeloma (MM) cells and considered an ideal target for immunotherapeutic approaches. Indeed, elotuzumab, an anti-SLAMF7 antibody, is used for the treatment of MM in combination with immunomodulatory drugs. SLAMF7 is cleaved via unknown mechanisms and detected as a soluble form (sSLAMF7) exclusively in the serum of MM patients; however, little is known about the role of sSLAMF7 in MM biology. In this study, we found that sSLAMF7 enhanced the growth of MM cells via homophilic interaction with surface SLAMF7 and subsequent activation of the SHP-2 and ERK signaling pathways. Elotuzumab suppressed sSLAMF7-induced MM cell growth both in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the SLAMF7 gene. Pharmacological targeting of Ikaros by lenalidomide and its analog pomalidomide downregulated SLAMF7 expression and ameliorated the response of MM cells to sSLAMF7. Elotuzumab blocked the growth-promoting function of sSLAMF7 when combined with lenalidomide in a murine xenograft model. Neutralization of sSLAMF7 is a novel antimyeloma mechanism of elotuzumab, which is enhanced by immunomodulatory drugs via downregulation of surface SLAMF7 expression on MM cells. These findings may provide important information for the optimal use of elotuzumab in MM treatment.
Assuntos
Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Humanos , Lenalidomida/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Talidomida/análogos & derivados , Talidomida/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A 78-year-old man who had a 20-year history of polycythemia vera (PV) with a JAK2 V617F mutation presented with gradually progressive disturbance of consciousness. Hyper-intense lesions in the peri-lateral ventricular area and left cerebellar hemisphere were observed by T2-weighted and fluid-attenuated inversion recovery magnetic resonance imaging. Cytologic and genetic analyses of the lymphoma cells obtained from his cerebrospinal fluid established the diagnosis of B-cell lymphoma. No lesions outside of the brain were recognized. Because of his poor general condition, he was not treated actively. A postmortem analysis revealed a JAK2 V617F mutation in the lymphoma cells, suggesting their origin was a PV clone.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , DNA de Neoplasias/genética , Janus Quinase 2/genética , Linfoma/genética , Mutação , Policitemia Vera/complicações , Idoso , Biópsia , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/etiologia , Análise Mutacional de DNA , Evolução Fatal , Humanos , Janus Quinase 2/metabolismo , Linfoma/diagnóstico , Linfoma/etiologia , Imageamento por Ressonância Magnética , Masculino , Policitemia Vera/diagnóstico , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
Lymph node metastasis is one of the most important factors for tumor dissemination. Quantifying microRNA (miRNA) expression using real-time PCR in formalin-fixed, paraffin-embedded (FFPE) lymph node can provide valuable information regarding the biological research for cancer metastasis. However, a universal endogenous reference gene has not been identified in FFPE lymph node. This study aimed to identify suitable endogenous reference genes for miRNA expression analysis in FFPE lymph node. FFPE lymph nodes were obtained from 41 metastatic cancer and from 16 non-cancerous tissues. We selected 10 miRNAs as endogenous reference gene candidates using the global mean method. The stability of candidate genes was assessed by the following four statistical tools: BestKeeper, geNorm, NormFinder, and the comparative ΔCt method. miR-103a was the most stable gene among candidate genes. However, the use of a single miR-103a was not recommended because its stability value exceeded the reference value. Thus, we combined stable genes and investigated the stability and the effect of gene normalization. The combination of miR-24, miR-103a, and let-7a was identified as one of the most stable sets of endogenous reference genes for normalization in FFPE lymph node. This study may provide a basis for miRNA expression analysis in FFPE lymph node tissue.
Assuntos
Metástase Linfática/genética , MicroRNAs/genética , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Formaldeído , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , MicroRNAs/classificação , Pessoa de Meia-Idade , Neoplasias/classificação , Neoplasias/patologia , Inclusão em Parafina , Fixação de TecidosRESUMO
We report two complete proviral genome sequences of human T-cell leukemia virus type 1 (HTLV-1) isolated from the peripheral blood specimens of acute type adult T-cell leukemia (ATL) patients in Oita Prefecture, Japan.
RESUMO
A 55-year-old man presented to our department with diarrhea, weight loss, fatigability, and polyarthralgia. Blood tests revealed elevated soluble interleukin-2 receptor levels and IgG-type M protein positivity, without any findings that were suggestive of collagen disease. After computed tomography (CT) detected enlarged lymph nodes in the abdominal para-aortic region, lymphoma was suspected. CT-guided needle biopsy of the lymph node did not help to achieve a definitive diagnosis; however, a bone marrow test showed the pathological features of B-cell lymphoma. A genetic examination detected a MYD88 L265P mutation; the mutation analysis was valuable in diagnosing lymphoplasmacytic lymphoma in a IgM-type M protein-negative patient.
Assuntos
Fator 88 de Diferenciação Mieloide/genética , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Medula Óssea/patologia , Análise Mutacional de DNA , Diagnóstico Diferencial , Glicoproteínas/biossíntese , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Interleucina-2/biossíntese , Macroglobulinemia de Waldenstrom/patologiaAssuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Família de Moléculas de Sinalização da Ativação Linfocitária/sangue , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Humanos , Mieloma Múltiplo/diagnóstico , Prognóstico , Resultado do TratamentoRESUMO
In normal human germinal centre (GC) B-cells and post-GC B-cell lymphomas, a region in the first intron of the BCL6 gene, termed the major mutations cluster (MMC) exhibits somatic point mutations and deletions with patterns very similar to those seen in the variable regions of immunoglobulin (Ig) genes. In studies of mouse post-GC diffuse large cell lymphoma, Burkitt lymphomas, and plasmacytomas, direct sequencing or cold SSCP analyses revealed no mutations within a 686-bp region in Bcl6 intron 1 with 72% identity to the human MMC. The mouse Bcl6 locus must be inaccessible to the mutational machinery responsible for somatic mutations of Ig and BCL6 in humans.
Assuntos
Proteínas de Ligação a DNA/genética , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Animais , Linhagem da Célula , Análise Mutacional de DNA , Humanos , Íntrons , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Congênicos , Mutação , Proteínas Proto-Oncogênicas c-bcl-6 , Homologia de Sequência do Ácido NucleicoRESUMO
Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-κB by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3), CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1) exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced 'germ free' status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named 'pseudo-infective endocarditis' were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction.
Assuntos
Endocardite/microbiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microbiota , Proteínas de Neoplasias/genética , Animais , Antibacterianos/uso terapêutico , Sequência de Bases , Doença Crônica , Primers do DNA , Endocardite/tratamento farmacológico , Endocardite/genética , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
The correlation between imatinib (IM) trough plasma concentration (Cmin) and clinical response was assessed in patients with chronic-phase chronic myeloid leukemia. The Cmin correlated with neither the achievement of complete cytogenetic response (977 vs. 993 ng/ml, P = 0.48) nor a major molecular response (1,044 vs. 818 ng/ml, P = 0.17). Although this was significantly higher in patients with complete molecular response (CMR) than in those without (1,430 vs. 859 ng/ml, P = 0.04), the difference was not significant in the sub-population treated with a standard dose of IM (400 mg/day). Finally, multivariate analysis showed that the IM standard dose, but not Cmin, was predictive of the achievement of CMR. We thus suggest that, in practical clinics at least, adherence to the standard dose is the most important factor for the achievement of CMR.
Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mieloide de Fase Crônica/sangue , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacocinética , Idoso , Benzamidas , Estudos Transversais , Análise Citogenética , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Feminino , Proteínas de Fusão bcr-abl/sangue , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Japão , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/sangue , Proteínas Tirosina Quinases/genética , Pirimidinas/administração & dosagem , Indução de Remissão/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Langerhans cell sarcoma (LCS), a neoplastic proliferation of Langerhans cells with malignant cytologic features, is a very rare disease. We report the case of a 62-year-old male with LCS arising in a cervical lymph node. Histologic examination of a biopsy specimen of the lymph node demonstrated a proliferation of Langerhans cells with malignant cytologic features. Immunohistochemically, the tumor cells were positive for S-100 protein, CD1a, and Langerin (CD207). These histomorphological findings supported the diagnosis of LCS. The patient underwent radiotherapy. Neither local recurrence nor distant metastasis was observed at 45 months after radiotherapy. Characteristic immunohistochemical findings were helpful to identify LCS, and head and neck surgeons should be aware of this rare disease entity.