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Peripheral neuropathy (PN), a debilitating complication of diabetes, is associated with obesity and the metabolic syndrome in nondiabetic individuals. Evidence indicates that a high fat diet can induce signs of diabetic peripheral PN in mice but the pathogenesis of high fat diet-induced PN remains unknown. PURPOSE: Determine if neuronal inflammation is associated with the development of mechanical hypersensitivity and nerve fiber changes in high fat fed mice. METHODS: Male C57Bl/6 mice were randomized to a standard (Std, 15% kcal from fat) or high fat diet (HF, 54% kcal from fat) for 2, 4, or 8 weeks (n = 11-12 per group). Lumbar dorsal root ganglia were harvested and inflammatory mediators (IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-17, MCP-1, IFN-γ, TNF-α, MIP-1α, GMCSF, RANTES) were quantified. Hindpaw mechanical sensitivity was assessed using the von Frey test. Intraepidermal nerve fiber density (IENFD) and TrkA nerve fiber density were quantified via immunohistochemistry. RESULTS: After 8 weeks, HF had greater body mass (33.3 ± 1.0 vs 26.7 ± 0.5 g, p < 0.001), fasting blood glucose (160.3 ± 9.4 vs 138.5 ± 3.4 mg/dl, p < 0.05) and insulin (3.58 ± 0.46 vs 0.82 ± 0.14 ng/ml, p < 0.001) compared to Std. IL-1α, RANTES and IL-5 were higher in HF compared to Std after 2 and 4 weeks, respectively (IL-1α: 4.8 ± 1.3 vs 2.9 ± 0.6 pg/mg, p < 0.05; RANTES: 19.6 ± 2.2 vs 13.3 ± 1.2 pg/mg p < 0.05; IL-5: 5.8 ± 0.7 vs 3.1 ± 0.5 pg/mg, p < 0.05). IENFD and TrkA fiber density were also higher in HF vs Std after 4 weeks (IENFD: 39.4 ± 1.2 vs 32.2 ± 1.3 fibers/mm, p < 0.001; TrkA: 30.4 ± 1.8 vs 22.4 ± 1.3 fibers/mm). There were no significant differences in hindpaw sensitivity for Std vs HF. CONCLUSION: Increased inflammatory mediators preceded and accompanied an increase in cutaneous pain sensing nerve fibers in high fat fed mice but was not accompanied by significant mechanical allodynia. Diets high in fat may increase neuronal inflammation and lead to increased nociceptive nerve fiber density.
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Exposure to ionizing radiation increases the risk of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but such risks are not known in well-differentiated thyroid cancer (WDTC) patients treated with radioactive iodine (RAI). A total of 148 215 WDTC patients were identified from Surveillance, Epidemiology and End Results registries between 1973 and 2014, of whom 54% underwent definitive thyroidectomy and 46% received adjuvant RAI. With a median follow-up of 6.6 years, 77 and 66 WDTC patients developed MDS and MPN, respectively. Excess absolute risks for MDS and MPN from RAI treatment when compared to background rates in the US population were 6.6 and 8.1 cases per 100 000 person-years, respectively. Compared to background population rates, relative risks of developing MDS (3.85 (95% confidence interval, 1.7-7.6); P=0.0005) and MPN (3.13 (1.1-6.8); P=0.012) were significantly elevated in the second and third year following adjuvant RAI therapy, but not after thyroidectomy alone. The increased risk was significantly associated with WDTC size ⩾2 cm or regional disease. Development of MDS was associated with shorter median overall survival in WDTC survivors (10.3 vs 22.5 years; P<0.001). These data suggest that RAI treatment for WDTC is associated with increased risk of MDS with short latency and poor survival.
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Isótopos de Iodo/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Transtornos Mieloproliferativos/etiologia , Neoplasias da Glândula Tireoide/radioterapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tireoidectomia/métodos , Adulto JovemAssuntos
Negro ou Afro-Americano/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteína Supressora de Tumor p53/genética , População Branca/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Estados Unidos/epidemiologiaAssuntos
Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Prognóstico , Adulto JovemRESUMO
The biology, clinical phenotype and progression rate of chronic myelomonocytic leukemia (CMML) are highly variable due to diverse initiating and secondary clonal genetic events. To determine the effects of molecular features including clonal hierarchy in CMML, we studied whole-exome and targeted next-generation sequencing data from 150 patients with robust clinical and molecular annotation assessed cross-sectionally and at serial time points of disease evolution. To identify molecular lesions unique to CMML, we compared it to the related myeloid neoplasms (N=586), including juvenile myelomonocytic leukemia, myelodysplastic syndromes (MDS) and primary monocytic acute myeloid leukemia and discerned distinct molecular profiles despite similar pathomorphological features. Within CMML, mutations in certain pathways correlated with clinical classification, for example, proliferative vs dysplastic features. While most CMML patients (59%) had ancestral (dominant/co-dominant) mutations involving TET2, SRSF2 or ASXL1 genes, secondary subclonal hierarchy correlated with clinical phenotypes or outcomes. For example, progression was associated with acquisition of new expanding clones carrying biallelic TET2 mutations or RAS family, or spliceosomal gene mutations. In contrast, dysplastic features correlated with mutations usually encountered in MDS (for example, SF3B1 and U2AF1). Classification of CMML based on hierarchies of ancestral and subclonal mutational events may correlate strongly with clinical features and prognosis.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Leucemia Mielomonocítica Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Aberrações Cromossômicas , Evolução Clonal , Hibridização Genômica Comparativa , Estudos Transversais , Feminino , Frequência do Gene , Genômica/métodos , Humanos , Cariótipo , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Sequenciamento do ExomaRESUMO
This corrects the article DOI: 10.1038/leu.2016.276.
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INTRODUCTION: The t(6;9)(p23;q34);DEK-NUP214 [t(6;9)] abnormality is found in 0.7-1.8% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). FLT3-ITD mutations are detected in t(6;9) patients. The t(6;9) abnormality is associated with poor outcomes. We studied the clinicopathologic and molecular profiles of patients with AML/MDS carrying t(6;9). METHODS: We collected clinical data of nine patients with AML/MDS with isolated t(6;9) (median age = 41 years; male/female = 4/5) and genotyped DNAs using whole exome, Sanger, and targeted sequencing. RESULTS: Our cohort was characterized by frequent multilineage dysplasia (56%), absence of phospho-STAT3/STAT5 expression, presence of myeloid markers (CD13, CD33, CD34, CD117, HLA-DR) with an aberrant expression of CD7, and poor outcome (median survival of 20 months). Although basophilia has been described in association with t(6;9), we observed lack of marrow basophilia in our cohort. Molecularly, 83% (5/6) of patients with AML/MDS with t(6;9) were characterized by at least one somatic mutation. Among them, four patients showed multiple mutations. FLT3-ITD mutations were detected in 33% of patients (2/6); 80% (4/5) of mutant patients died even after hematopoietic stem cell transplantation. CONCLUSION: Our data demonstrated that AML/MDS patients with t(6;9) have diverse molecular mutations regardless of the presence of FLT3 mutations, which may contribute to their poor survival outcomes.
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Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Translocação Genética , Adulto , Idoso , Biópsia , Medula Óssea/patologia , Exoma , Feminino , Duplicação Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Imunofenotipagem , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Sequências de Repetição em Tandem , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaAssuntos
Deleção de Genes , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Animais , Cromossomos Humanos Par 20 , Estudos de Coortes , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Camundongos , Camundongos KnockoutRESUMO
Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML). Overall, mutations in FLT3, DNMT3A, NPM1 and IDH2 were more specific for pAML whereas UTAF1, STAG2, BCORL1, BCOR, EZH2, JAK2, CBL, PRPF8, SF3B1, ASXL1 and DHX29 were more specific for sAML. However, in multivariate analysis that included clinical variables, only FLT3 and DNMT3A remained specific for pAML and EZH2, BCOR, SF3B1 and ASXL1 for sAML. When the impact of mutations on OS was evaluated in the entire cohort, mutations in DNMT3A, PRPF8, ASXL1, CBL EZH2 and TP53 had a negative impact on OS; no mutation impacted OS favorably; however, in a cox multivariate analysis that included clinical data, mutations in DNMT3A, ASXL1, CBL, EZH2 and TP53 became significant. Thus, controlling for clinical variables is important when interpreting genomic data in AML.
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Genômica , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Prognóstico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Mutação/genética , NucleofosminaAssuntos
Fatores Imunológicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 5 , Estudos de Coortes , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Talidomida/uso terapêutico , Adulto JovemRESUMO
The Revised International Prognostic Scoring System (IPSS-R) was developed for untreated myelodysplastic syndrome (MDS) patients based on clinical data. We created and validated a new model that incorporates mutational data to improve the predictive capacity of the IPSS-R in treated MDS patients. Clinical and mutational data from treated MDS patients diagnosed between January 2000 and January 2012 were used to develop the new prognostic system. A total of 508 patients were divided into training (n=333) and validation (n=175) cohorts. Independent significant prognostic factors for survival included age, IPSS-R, EZH2, SF3B1 and TP53. Weighted coefficients for each factor were used to build the new linear predictive model, which produced four prognostic groups: low, intermediate-1, intermediate-2 and high with a median overall survival of 37.4, 23.2, 19.9 and 12.2 months, respectively, P<0.001. Significant improvement in the C-index of the new model (0.73) was observed compared with the IPSS-R (0.69). The new model predicted outcome both in a separate validation cohort and in another cohort of patients with paired samples at different time points during their disease course. The addition of mutational data to the IPSS-R makes it dynamic and enhances its predictive ability in treated MDS patients regardless of their initial or subsequent therapies.
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Modelos Biológicos , Síndromes Mielodisplásicas/diagnóstico , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Medição de Risco/normas , Taxa de Sobrevida , Adulto JovemRESUMO
Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
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Proteínas de Ligação a DNA/biossíntese , Epigênese Genética , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/metabolismo , Fatores de Transcrição/biossíntese , Acetilação , Animais , Carcinogênese/genética , Proteínas de Ligação a DNA/deficiência , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Histona Acetiltransferases/antagonistas & inibidores , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Síndromes Mielodisplásicas/genética , Proteínas de Fusão Oncogênica , Prognóstico , Fatores de Transcrição/deficiênciaRESUMO
Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk (HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P=0.025 for the IPSS, P=0.011 for WPSS and P<0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11-16 months and should be considered for up-front transplantation or experimental approaches.
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Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Bases de Dados Factuais , Decitabina , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Prognóstico , Projetos de Pesquisa , Fatores de Risco , Análise de SobrevidaRESUMO
Risks of acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) are known to increase after cancer treatments. Their rise-and-fall dynamics and their associations with radiation have, however, not been fully characterized. To improve risk definition we developed SEERaBomb R software for Surveillance, Epidemiology and End Results second cancer analyses. Resulting high-resolution relative risk (RR) time courses were compared, where possible, to results of A-bomb survivor analyses. We found: (1) persons with prostate cancer receiving radiation therapy have increased RR of AML and MDS that peak in 1.5-2.5 years; (2) persons with non-Hodgkin lymphoma (NHL), lung and breast first cancers have the highest RR for AML and MDS over the next 1-12 years. These increased RR are radiation specific for lung and breast cancer but not for NHL; (3) AML latencies were brief compared to those of A-bomb survivors; and (4) there was a marked excess risk of acute promyelocytic leukemia in persons receiving radiation therapy. Knowing the type of first cancer, if it was treated with radiation, the interval from first cancer diagnosis to developing AML or MDS, and the type of AML, can improve estimates of whether AML or MDS cases developing in this setting are due to background versus other processes.