RESUMO
Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.
Assuntos
Leucemia Mieloide Aguda , Proteína Supressora de Tumor p53 , Variações do Número de Cópias de DNA , Epigênese Genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Prognóstico , Proteômica , Proteína Supressora de Tumor p53/genéticaRESUMO
Atmospheric deposition of Cd poses a serious threat to ecosystem security. Biochar is widely used for polluted soil remediation, however, whether biochar already applied to the soil can reduce the hazards of newly deposited Cd remains to be studied. Thus, an indoor cultural experiment and static adsorption method were conducted to study the isothermal and kinetic adsorption processes of three types of biochar (rice husk, rubber wood, and tobacco stem biochars) on Cd in iron rich soils and the effect of biochar on the morphological distribution of Cd in the soil and the soil pH. The results showed that the soil with biochar in our study could quickly fix "the new deposited Cd" in the soil in 3 h with the maximum adsorption capacity in rubber wood biochar-treated sample (3227.34 mg/kgï¼. The addition of all three biochar treatments significantly increased the soil pH and reduced the soil exchange state Cd content, with a 13.69-17.32% increase in the pH and a 13.22-54.39% reduction in the exchange state Cd content when contrasted with the control, which could promote those Cd converting into unavailable Cd (carbonate-bound form Cd, Fe-Mn oxide-bound form Cd, or residual form Cd) for crops. In summary, the addition of three kinds of biochar treatments could effectively reduce the ecological and environmental risk of soil that was contaminated by Cd and could provide a reliable theoretical basis for the effect of biochar on the improvement of the quality of soil that is contaminated by heavy metals.
Assuntos
Cádmio , Poluentes do Solo , Cádmio/análise , Ferro , Solo/química , Ecossistema , Poluentes do Solo/análise , Carvão Vegetal/químicaRESUMO
BACKGROUND: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood. METHODS: The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL. RESULTS: The median age was 43 years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), CD10 (25%), CD56 (partial, 19%), and CD4 (6%). Cytogenetic analyses revealed a diploid karyotype in 10 patients, simple (1-2) abnormalities in 10 patients, and complex karyotype in 10 patients. Next-generation sequencing for 21 patients demonstrated that all had gene mutations (median, four mutations per patient). The most frequently mutated genes were WT1 (38%), NOTCH1 (29%), NRAS (29%), PHF6 (25%), TP53 (24%), ASXL1 (19%), FLT3 (19%), and IKZF1 (19%). All patients except one received multi-agent chemotherapy, and 22 patients underwent allogeneic stem cell transplantation. Thrombocytopenia, an abnormal karyotype, and TP53 mutation were associated with markedly shortened overall survival. Stem cell transplantation significantly improved overall survival. CONCLUSIONS: Patients with ETP-ALL often have high mutation burden with increased genomic instability. TP53 mutation was the only molecular prognostic marker and was associated with complex karyotype and greater than or equal to five mutations. These patients may benefit from stem cell transplantation, and recurrent gene mutations may be novel therapeutic markers.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Células Precursoras de Linfócitos T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Imunofenotipagem , PrognósticoRESUMO
DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P<0.05). TP63 rearrangement (TP63-R) was detected in three of the 66 (5%) ALK-negative ALCL cases tested and none of these cases carried the DUSP22-R. Overall survival of patients with DUSP22-R ALCL was similar to that of the patients with DUSP22-NR neoplasms regardless of International Prognostic Index score, stage, age, or stem cell transplantation status (all P>0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.
Assuntos
Linfoma Anaplásico de Células Grandes , Receptores Proteína Tirosina Quinases , Humanos , Quinase do Linfoma Anaplásico/genética , Receptores Proteína Tirosina Quinases/genética , Linfoma Anaplásico de Células Grandes/patologia , Imunofenotipagem , Prognóstico , Fosfatases de Especificidade Dupla/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genéticaRESUMO
Lymphomatoid papulosis (LyP) with DUSP22-IRF4 rearrangement is a rare, recently described variant of LyP histopathologically characterized by a biphasic growth pattern, with epidermotropic small-to-medium-sized atypical T-cells and dermal large and transformed T-cells diffusely expressing CD30. LyP with DUSP22-IRF4 rearrangement can mimic other cutaneous lymphoproliferative disorders, particularly primary cutaneous anaplastic large cell lymphoma (PCALCL) or transformed mycosis fungoides (MF). Unlike PCALCL or transformed MF, LyP with DUSP22-IRF4 rearrangement shows an indolent clinical behavior, with frequent spontaneous regression of untreated lesions. Thus, it is important to recognize this rare variant of LyP to avoid misclassification, which may potentially lead to unnecessarily aggressive patient management. To our knowledge, only 13 cases of LyP with DUSP22-IRF4 rearrangement have been reported to date in the English literature. Herein, we describe an additional case of LyP with DUSP22-IRF4 rearrangement in a 63-year-old man and provide a comprehensive literature review with regards to the clinical, histopathologic, and molecular features of this novel entity.
Assuntos
Papulose Linfomatoide , Micose Fungoide , Neoplasias Cutâneas , Masculino , Humanos , Pessoa de Meia-Idade , Papulose Linfomatoide/genética , Papulose Linfomatoide/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Micose Fungoide/patologia , Linfócitos T/patologia , Antígeno Ki-1 , Fosfatases de Especificidade Dupla/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genéticaRESUMO
Burkitt lymphoma (BL) is a mature B-cell neoplasm arising from germinal center B-cells. There are three epidemiological variants of which the sporadic variant is most prevalent in developed countries representing 1-2 % of all lymphomas in adults. Patients usually present with bulky abdominal masses and ~ 30 % have bone marrow involvement. BL is characterized by a germinal center B-cell immunophenotype and usually has a simple karyotype. Here we report an unusual case of sporadic BL in a 44-year-old man and we use this case to review sporadic BL in adults. The patient presented with a cecal mass and bone marrow involvement. Biopsy of the cecal mass and bone marrow evaluation showed infiltration by intermediate-size lymphoma cells positive for monotypic kappa, CD10, CD19, CD20, CD22, CD38 bright, CD43, CD45, Bcl6 and ROR1, and negative for CD11c, CD23, CD30, CD44, CD200 and Bcl2. As expected, the lymphoma cells were strongly positive for MYC and Ki-67 showed a proliferation rate of nearly 100 %, but the cells were also positive for SOX11 and cytoplasmic LEF1. Conventional chromosomal analysis revealed t(8;14) as part of a complex karyotype. Based on our literature review, and is shown in this case, sporadic BL in adults shows some differences with the classic description of BL in children. We also discuss the differential diagnosis of BL.
Assuntos
Linfoma de Burkitt , Linfoma de Células B , Linfoma , Masculino , Criança , Adulto , Humanos , Linfoma de Burkitt/genética , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , Translocação Genética , Linfoma de Células B/patologia , Cariótipo , Fatores de Transcrição SOXC/genéticaRESUMO
Fluorescence in situ hybridization analysis (FISH) using a CBFB breakapart probe is widely used to detect CBFB rearrangement (CBFBr) in cases of acute myeloid leukemia (AML). However, detection of 3'CBFB deletion (3'CBFBdel) often poses a challenge for interpretation, and the clinical importance of 3'CBFBdel associated CBFBr remains largely unknown. We identified 16 AML patients with 3'CBFBdel, 11 (69%) of which were confirmed to have CBFB::MYH11 fusion. These 11 patients presented with de novo AML; 10 showed myelomonocytic differentiation, 8 had a prominent eosinophilic component, and 7 showed characteristic eosinophils with basophilic granules. Next generation sequencing showed mutations in 7/8 patients, 5 with KRAS/NRAS, 3 with FLT3-TKD, but none with KIT mutations. Except for one patient who died 5 days after diagnosis of AML, all 10 patients received chemotherapy and achieved remission initially. However, within 3 years, 5 (50%) patients had relapsed, of whom, 1 died and 4 received hematopoietic stem cell transplant. After a median follow-up of 76 months, 3 patients died and 8 were alive in complete remission. Our study shows that detection of 3'CBFBdel is not equivalent to unbalanced CBFB rearrangement, and therefore, an alternative confirmatory test is warranted. AML with 3'CBFBdel/CBFBr often shows similar pathological features to AML with inv(16), but appears to have different mutation profiles and a higher risk of relapse requiring hematopoietic stem cell transplant.
Assuntos
Subunidade beta de Fator de Ligação ao Core , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Inversão Cromossômica , Cromossomos Humanos Par 16 , Subunidade beta de Fator de Ligação ao Core/genética , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Proteínas de Fusão Oncogênica/genética , Recidiva , Deleção de SequênciaRESUMO
Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive form of large B-cell lymphoma that is preferentially located within blood vessel lumina. Despite its intravascular location, a leukemic phase of disease seems to be uncommon. After encountering a patient with IVLBCL with numerous circulating lymphoma cells, we reviewed the literature and identified 6 patients with IVLBCL who had numerous circulating lymphoma cells (defined by ≥10% lymphoma cells in peripheral blood). The percentage of circulating lymphoma cells in this patient cohort was variable, with a median of 36% (range, 14% - 87%), Bone marrow was involved in all 5 patients assessed. Elevation of liver transaminases preferentially affecting aspartate aminotransferase (AST, 3/3, 100%), hepatosplenomegaly (4/5, 80%), thrombocytopenia (100%), CD5 positivity (100%) and monotypic lambda light chain predominance (3/4, 75%) were common features. Conventional cytogenetic analysis performed in 4 patients revealed a complex karyotype with multiple abnormalities particularly deletions and copy number aberrations involving chromosomes 6q and 18. The clinical courses of these patients were highly variable, but overall there was a high mortality rate of 75% with 18-months of follow-up. Due to the rarity of IVLBCL, along with its variable clinical manifestations and subtle pathologic changes, the diagnosis is often delayed which may contribute to the poor outcome of IVLBCL patients. Recognition that this disease can present rarely with a leukemic phase further expands our knowledge of the clinicopathologic spectrum of IVLBC.
Assuntos
Linfoma Difuso de Grandes Células B , Medula Óssea/patologia , Humanos , Fígado/patologia , Linfócitos/patologia , Linfoma Difuso de Grandes Células B/patologiaRESUMO
The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients.
Assuntos
Neoplasias Hematológicas , Isocromossomos , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Neoplasias Hematológicas/genética , Humanos , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Sporadic reports of t(3;12)(q26.2;p13) indicate that this abnormality is associated with myeloid neoplasms, myelodysplasia, and a poor prognosis. To better characterize neoplasms with this abnormality, we assessed 20 patients utilizing clinicopathological data, cytogenetic, and targeted next-generation sequencing analysis. We also performed literature review of 58 prior reported cases. Patients included ten men and ten women with median age 55.8 years (range, 27.8-78.8). Diagnoses included 11 acute myeloid leukemia (AML, 5 de novo and 6 secondary), 5 myelodysplastic syndromes (MDS, 3 de novo excess blasts-2 and 2 therapy-related), 2 chronic myeloid leukemia BCR-ABL1-positive blast phase (1 de novo and 1 secondary), 1 primary myelofibrosis (secondary), and 1 mixed-phenotype acute leukemia T/myeloid (MPAL, secondary). Morphologic dysplasia was identified in all AML cases (5/5), MDS cases (4/4), therapy-related cases (3/3), half of myeloproliferative neoplasm cases (1/2), and one MPAL case assessed. The t(3;12) was detected de novo and in subsequent workups in 9 and 11 patients, respectively. Seven patients had t(3;12) only and eight patients had additional chromosome 7 abnormalities. Fluorescence in-situ hybridization detected MECOM (n = 11) and ETV6 (n = 7) rearrangements in all cases assessed. FLT3 internal tandem duplication was identified in five (25%) patients. We identified 13 genetic abnormalities in the de novo group (n = 9), and 25 in the secondary disease group (n = 11). All patients received chemotherapy, with seven allogeneic and two autologous stem cell transplantations. At last follow-up, 14 (70%) patients died with median survival of 6.3 months (range, 0.1-17.3) after detection of t(3;12). In summary, t(3;12)(q26.2;p13) is a rare cytogenetic abnormality in myeloid neoplasms. Myelodysplasia, chromosome 7 abnormalities, and high blast counts are common, and the prognosis is poor. Given the close relationship between the presence of this cytogenetic abnormality and the MDS-related changes, we recommend adding t(3;12)(q26.2;p13) to the list of AML with myelodysplasia-related changes defining abnormalities of the World Health Organization 2017 classification of myeloid neoplasms.
Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/patologia , Translocação GenéticaRESUMO
MET amplification has been associated with shorter survival in cancer patients and thought to represent one of two major mechanisms for developing resistance to therapy with EGFR inhibitors. We retrospectively studied 99 patients who had non-small cell lung cancer (NSCLC) and had at least two FISH analyses for MET/CEP7 at different time points during the course of disease. Four (4%) patients showed MET amplification in the initial diagnostic biopsy, and 16 (16%) patients acquired MET amplification in the follow-up biopsy specimens. Acquired MET amplification was highly associated with EGFR inhibitor treatment. Except for EGFR and TP53 mutations, other gene mutations were rare in the patients with MET amplification. Patients with acquired MET amplification showed no significant survival difference comparing to the patients who did not show MET amplification.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Leukemic, non-nodal mantle cell lymphoma (MCL) is a distinct, rare, indolent variant of mantle cell lymphoma, but can relapse aggressively. It can present with lymphocytosis with chronic lymphocytic leukemia (CLL)-like morphologic and immunophenotypic features as was initially considered in the index case. However, at time of splenectomy, two years later cyclin D1 overexpression was shown and the disease was realized to be leukemic non-nodal MCL. The patient was followed for 21 years, without therapy, before he developed clinically aggressive MCL with lymphadenopathy. Lymph node biopsy showed MCL, pleomorphic variant. We review the literature and discuss the features of leukemic non-nodal MCL as well as the potential pitfalls in diagnosis. Furthermore, we are not aware of another cases reported with a 21 year interval from initial diagnosis of leukemic non-nodal MCL to aggressive MCL.
Assuntos
Ciclina D1/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Seguimentos , Humanos , Imunofenotipagem/métodos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfadenopatia/patologia , Linfocitose/etiologia , Linfocitose/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/terapia , Masculino , Recidiva , Indução de Remissão , Esplenectomia/métodos , Transplante de Células-Tronco/métodos , Transplante Homólogo/métodosRESUMO
Cybercriminals are taking advantage of the COVID-19 outbreak and offering COVID-19-related scams to unsuspecting people. Currently, there is a lack of studies that focus on protecting people from COVID-19-related cybercrimes. Drawing upon Cultivation Theory and Protection Motivation Theory, we develop a research model to examine the cultivation effect of government social media on peoples' information security behavior towards COVID-19 scams. We employ structural equation modeling to analyze 240 survey responses collected from social media followers of government accounts. Our results suggest that government social media account followers' participation influences their information security behavior through perceived severity, perceived vulnerability, self-efficacy, and response efficacy. Our study highlights the importance of government social media for information security management during crises.
RESUMO
Acute myeloid leukemia (AML) with intrachromosomal amplification of chromosome 21 (iAMP21) is rare and has not been well characterized. We report 13 patients, 7 men and 6 women, with a median age of 65 years. Eleven patients presented with AML with myelodysplasia-related changes, and two patients had therapy-related AML. Cytopenias were detected in all patients (11 pancytopenia and two bi-lineage cytopenia). Myelodysplastic changes were observed in all 11 patients with adequate cells to evaluate. Myelofibrosis was present in ten patients. All patients had a complex karyotype, including abnormalities of chromosomes 5, 7, 17, and hsr(21)(q22), and ten patients showed TP53 deletion and/or mutation. Eleven patients received AML-based chemotherapy, one of whom also received hematopoietic stem cell transplant. By the end of the last follow-up, eight patients died with median survival of 3.2 months, four patients were alive with persistent AML, and one was in complete remission. The median overall survival was 6 months for all patients. We conclude that AML with iAMP21 is often associated with cytopenias, myelodysplasia, a complex karyotype, TP53 mutation/deletion, and a poor prognosis despite current therapies.
Assuntos
Cromossomos Humanos Par 21/genética , Leucemia Mieloide Aguda/genética , Proteína Supressora de Tumor p53/genética , Cariótipo Anormal , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Chromosomal insertion-derived BCR-ABL1 fusion is rare and mostly cryptic in chronic myeloid leukemia (CML). Most of these cases present a normal karyotype, and their risk and/or prognostic category are uncertain. We searched our database and identified 41 CML patients (20 M/21 F, median age: 47 years, range 12-78 years) with insertion-derived BCR-ABL1 confirmed by various FISH techniques: 31 in chronic phase, 1 in accelerated phase, and 9 in blast phase at time of diagnosis. Conventional cytogenetics analysis showed a normal karyotype (n = 19); abnormal karyotype with morphologically normal chromosomes 9 and 22 (n = 5); apparent ins(9;22) (n = 2) and abnormal karyotype with apparent abnormal chromosomes 9, der(9) and/or 22, der(22) (n = 15). The locations of insertion-derived BCR-ABL1 were identified on chromosome 22 (68.3%), 9 (29.3%), and 19 (2.4%). Complex chromosomal abnormalities were often overlooked by conventional cytogenetics but identified by FISH tests in many cases. After a median follow-up of 58 months (range 1-242 months), 11 patients died, and 3 lost contact, while the others achieved different cytogenetic/molecular responses. The locations of BCR-ABL1 (der(22) vs. non-der(22)) and the karyotype results (complex karyotype vs. noncomplex karyotype) by conventional cytogenetics were not associated with overall survival in this cohort. However, redefining the complexity of chromosomal abnormality by correlating karyotype and FISH findings, CML cases with simple chromosomal abnormalities had a more favorable overall survival than that with complex chromosomal abnormalities. We conclude that insertion-derived BCR-ABL1 fusions often involve complex chromosomal abnormalities which are overlooked by conventional cytogenetics, but can be identified by one or more FISH tests. We also suggest that the traditional cytogenetic response criteria may not apply in these patients, and the complexity of chromosomal abnormalities redefined by correlating karyotype and FISH findings can plays a role in stratifying patients into more suitable risk groups for predicting prognosis. (Word count: 292).
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Cariótipo Anormal , Adolescente , Adulto , Idoso , Criança , Aberrações Cromossômicas , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
BACKGROUND: Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification. METHODS: Mutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma. RESULTS: The proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival. CONCLUSIONS: The mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.
Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Medicina de Precisão , Prognóstico , Estudos Retrospectivos , Análise de Sequência de DNA , Análise de SobrevidaRESUMO
Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Feminino , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Lipase Lipoproteica/genética , Lipase Lipoproteica/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Piperidinas , Modelos de Riscos Proporcionais , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Medição de Risco , Rituximab/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Proteína Supressora de Tumor p53/deficiência , Proteína-Tirosina Quinase ZAP-70/biossíntese , Proteína-Tirosina Quinase ZAP-70/genéticaRESUMO
Human exposure to methylmercury (MeHg) through rice consumption is raising health concerns. It has long been recognized that MeHg found in rice grain predominately originated from paddy soil. Anaerobic conditions in paddy fields promote Hg methylation, potentially leading to high MeHg concentrations in rice grain. Understanding the transformation and migration of Hg in the rice paddy system, as well as the effects of farming activities, are keys to assessing risks and developing potential mitigation strategies. Therefore, this review examines the current state of knowledge on: 1) sources of Hg in paddy fields; 2) how MeHg and inorganic Hg (IHg) are transformed (including abiotic and biotic processes); 3) how IHg and MeHg enter and translocate in rice plants; and 4) how regular farming activities (including the application of fertilizer, cultivation methods, choice of cultivar), affect Hg cycling in the paddy field system. Current issues and controversies on Hg transformation and migration in the paddy field system are also discussed.
Assuntos
Produção Agrícola/métodos , Monitoramento Ambiental/métodos , Mercúrio/análise , Compostos de Metilmercúrio/análise , Oryza/efeitos dos fármacos , Poluentes do Solo/análise , Fertilizantes/análise , Humanos , Mercúrio/metabolismo , Compostos de Metilmercúrio/metabolismo , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Solo/química , Poluentes do Solo/metabolismoRESUMO
This study aimed to reinforce the barrier performance (i.e., oxygen-gas and water-vapor permeability) of poly(lactic acid) (PLA)-based films. Acetyltributylcitrate and zinc oxide nanoparticle (nano-ZnO), serving as plasticizer and nanofiller, respectively, were blended into a PLA matrix through a solvent-volatilizing method. The structural, morphological, thermal, and mechanical performances were then studied. Scanning electron microscopic images showed a significant dispersion of nano-ZnO in PLA ternary systems with low nano-ZnO content. The interaction between PLA matrix and ZnO nanoparticles was further analyzed by Fourier-transform infrared spectroscopy. Wide-angle X-ray scattering spectroscopy demonstrated high compatibility between PLA matrix and ZnO nanoparticles. Mechanical property studies revealed good tensile strength and low flexibility. Differential scanning calorimetry curves proved that an amorphous structure mostly existed in PLA ternary systems. The improvements in barrier property and tensile strength indicated that the PLA/nano-ZnO composite films could be used for food packaging application.