Gain of 1q as a Potential Adverse Prognostic Marker in Myelodysplastic Syndrome: Comparison with International Prognostic Scoring System Variables

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3640-3640 ◽  
Author(s):  
Hyun-Kyung Park ◽  
Dong Soon Lee ◽  
Hye Ryun Lee ◽  
Han Ik Cho ◽  
Hyun Kyung Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Prognostic Marker ◽  
Median Survival ◽  
Survival Curve ◽  
International Prognostic Scoring System ◽  
Chromosomal Anomalies ◽  
Kaplan Meier ◽  
Meier Survival Curve ◽  
1Q Gain

Abstract The gain of the 1q region, which is a recurrent chromosomal aberration in B lymphoproliferative disorder, has been reported one of the most common anomalies in Korean myelodysplastic patients. Recently, risk based application of hypomethylating agents or tailored therapy in MDS rely on the prognostic variables of International Prognostic Scoring System (IPSS). To investigate the possibility of 1q gain as a new prognostic marker, we evaluated the prognostic impact of 1q gain, along with comparison with IPSS variables. A total of 117 patients with newly diagnosed MDS between 1997 and 2007 at the Seoul National University Hospital were investigated. Fluorescence in situ hybridization (FISH) studies with 5 specific probe(EGR1 for 5q31 deletion, D7S522 for 7q31 deletion, CEP8, D20S108 for 20q12 deletion, LSI 1p36/1q25 for 1q gain) and conventional G-banding karyotyping were performed on bone marrow aspirates. Other laboratory findings, such as hemoglobin(Hb), absolute neutrophil count(ANC), platelet count, bone marrow blast percent and IPSS score, and clinical data were collected through the individual medical records. The median age was 54 years and the male-to-female ratio was 1.4. Using WHO classification, refractory anemia(RA) was 27.4% and the other subgroups as follows: RA with ringed sideroblast(RARS), 3.4%; refractory cytopenia with multilineage dysplasia(RCMD), 8.5%; RCMD with ringed sideroblasts(RCMD-RS), 0.9%; RA with excess blasts-1(RAEB-1), 26.5%; RAEB-2, 31.6%; and 5q- syndrome, 1.7%. Cytogenetic abnormalities by FISH and G-banding were detected in 58 patients (49.6%). Most frequent anomaly was trisomy 8 occuring in 28 patients(23.9% of the 117 patients, 48.3% of the 58 patients with clonal cytogenetic abnormalities). Gain of 1q was the second common anomalies seen in 18 patients (15.4%) and other anomalies were −7/del7q (13.7%), −5/del5q (13.7%), and del20q (2.6%). G-banding showed gain of 1q in 7 cases, additional 11 patients with gain of 1q were revealed by FISH only. Patients with 1q gain showed a poor survival (median survival 23 months; n=18) compared to patients without 1q gain (median survival 60 months; p=0.02). EGR1 and D7S522 deletion by FISH also had a shorter median survival (8 months vs. 60 months p=0.0001, 16 months vs. 60 months p=0.005). The initial platelet count and blast count were found to affect overall survival, whereas CEP8 FISH, D20S108 FISH, Hb and ANC did not. Our results show that gain of 1q is associated with an adverse clinical outcome and can be considered as a poor cytogenetic risk factor of IPSS. In the Western study, the prevalence of 1q gain was low because most studies report G-banding result only. But it may be increased up to 2.5 fold higher by using FISH analysis in combination with G-banding. A gain of 1q could be a candidate as an adverse prognostic marker in clinical practice, which could help for risk-adapted therapies. Figure 1. Kaplan-Meier survival curve for chromosomal anomalies and IPSS. (A) gain of 1q. (B) −1/del(7q). (C) del(20q). Figure 1. Kaplan-Meier survival curve for chromosomal anomalies and IPSS. (A) gain of 1q. (B) −1/del(7q). (C) del(20q).

Cytoplasmic Nucleophosmin (NPMc+) Mutations and FMS-Like Tyrosine Kinase 3 (Flt3) Internal Tandem Duplication (ITD) Mutations Cooperate to Cause Leukemia In a Mouse Model

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 145-145 ◽  
Author(s):  
Rachel E. Rau ◽  
Daniel Magoon ◽  
Emily McIntyre ◽  
Li Li ◽  
Sarah Greenblatt ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Survival Curve ◽  
Erythroid Cells ◽  
Rt Pcr ◽  
Facs Analysis ◽  
Kaplan Meier ◽  
Meier Survival Curve

Abstract Abstract 145 NPMc+ mutations occur in up to 60% of adult and 20% of childhood acute myeloid leukemia (AML) with normal karyotype. Flt3 ITD mutations occur in 25% of adult and 15% of childhood AML. Flt3 ITD mutations occur twice as frequently in patients with NPMc+ mutations compared to those who lack a NPMc+ mutation. The presence of Flt3 ITD portends a poor prognosis. NPMc+ is associated with improved outcome, but only in the absence of a concomitant Flt3 ITD mutations. Given the high frequency with which these mutations occur together it is plausible that they cooperate to cause leukemia. However, this has yet to be demonstrated experimentally. To examine this, we crossed mice expressing a knock-in of an 18-bp ITD mutation in the juxtamembrane domain of the murine Flt3 gene (Flt3 wt/ITD) with transgenic mice expressing Flag-tagged type A NPMc+ mutation driven by the myeloid-specific human MRP8 promoter. Flt3wt/ITD mice develop a fatal myeloproliferative disorder (Li L, et al. Blood. 2008;111:3849-58) and NPMc+ transgenic mice develop a non-fatal myeloproliferation (Cheng K, et al. Blood. 2010;115-18), but neither develop leukemia, suggesting that cooperating events are required. Progeny were characterized by: 1) H&E staining of peripheral blood smears, bone marrow (BM) cytospins, and spleen sections; 2) FACS analysis of BM cells, splenocytes and thymocytes to determine the disease phenotype; 3) RT PCR to examine the expression of Flt3 ITD and NPMc+; and 4) immunofluorescence (IF) using an anti-Flag antibody to determine localization of the NPMc+ protein. Mice harboring both mutations develop acute leukemia with a median onset of 285 days (Figure 1). All the leukemic mice exhibit a moribund appearance, leukocytosis (mean WBC 69.3±32.7 vs 11.7±8.3K/μ L in wt/wt mice), splenomegaly (mean weight 0.63±0.3 vs 0.12±0.02g in wt/wt mice), anemia and thrombocytopenia. Four disease phenotypes based on FACS and histologic analysis have been observed (Figure 2). Thirty-three percent develop AML with infiltration of the BM and spleen with Mac1+/Gr1+ myeloblasts. Thiry-three percent develop T cell ALL with infiltration of BM, spleen, thymuses and other organs with abnormal CD3+/CD4+/CD8+ lymphoblasts. An additional 33% develop a mixed phenotype acute T/myeloid leukemia with both Mac1+/Gr1+ myeloblasts and CD3+/CD4+/CD8+ lymphoblasts. One mouse developed an undifferentiated acute leukemia with primitive blasts expressing no markers specific for either lymphoid or myeloid lineage. RT-PCR of bulk leukemia cells demonstrates expression of NPMc+ and Flt3 ITD. IF of BM cells from leukemic mice demonstrates cytoplasmic localization of the NPMc+ protein. In summary, we have utilized a mouse model to demonstrate that NPMc+ and Flt3 ITD mutations cooperate to cause leukemia. Many of the mice with both mutations develop myeloid leukemia with features similar to the human disease. There is also a striking incidence of T cell leukemia, which is particularly interesting as the NPMc+ mutation is driven by the myeloid-specific hMRP8 promotor. It is possible that there is aberrant expression of NPMc+ in lymphoid cells due to position effects of the transgene or the activation of an endogenous leukemogenic retrovirus. Other disease models using this promoter have documented similar phenomenon (Jaiswal, et al. PNAS. 2003;100:10002-7). There is a long latency of disease onset which may be due to a relatively low level of expression of NPMc+ or because additional genetic or epigenetic events are required. Perhaps the Flt3 ITD mutation causes proliferation and NPMc+ impairs DNA repair resulting in the accumulation of additional mutations that contribute to leukemogenesis. This mouse model provides the first in vivo model of NPMc+/Flt3 ITD+ leukemia. The model will allow for the further study of this disease entity, including the examination of involved pathways and the exploration for potential therapeutic targets. Kaplan-Meier Survival Curve. Mice with both NPMc+ and Flt3 ITD mutations have a median survival of 413 days. FACS analysis of leukemic mice BM cells and thymocytes. Mice with AML have cKit+/Mac1+/Gr1+ myelobasts. Mice with T cell ALL have infiltration of the BM, spleen (not shown) and thymus with CD3+/CD4+/CD8+ lymphoblasts. Mice with T/myeloid leukemia have both Mac1+/Gr1+ myeloblasts and CD3+/CD4+/CD8+ lymphoblasts. Leukemic mice have depletion of maturing Ter119+ erythroid cells. Figure 1 Kaplan-Meier Survival Curve. Mice with both NPMc+ and Flt3 ITD mutations have a median survival of 413 days. Figure 1. Kaplan-Meier Survival Curve. Mice with both NPMc+ and Flt3 ITD mutations have a median survival of 413 days. Figure 2 FACS analysis of leukemic mice BM cells and thymocytes. Mice with AML have cKit+/Mac1+/Gr1+ myelobasts. Mice with T cell ALL have infiltration of the BM, spleen (not shown) and thymus with CD3+/CD4+/CD8+ lymphoblasts. Mice with T/myeloid leukemia have both Mac1+/Gr1+ myeloblasts and CD3+/CD4+/CD8+ lymphoblasts. Leukemic mice have depletion of maturing Ter119+ erythroid cells. Figure 2. FACS analysis of leukemic mice BM cells and thymocytes. Mice with AML have cKit+/Mac1+/Gr1+ myelobasts. Mice with T cell ALL have infiltration of the BM, spleen (not shown) and thymus with CD3+/CD4+/CD8+ lymphoblasts. Mice with T/myeloid leukemia have both Mac1+/Gr1+ myeloblasts and CD3+/CD4+/CD8+ lymphoblasts. Leukemic mice have depletion of maturing Ter119+ erythroid cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Enforced Differentiation of Dnmt3a-Null Bone Marrow Leads to Failure with c-Kit Mutations Driving Leukemic Transformation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 837-837
Author(s):  
Hamza Celik ◽  
Cates Mallaney ◽  
Alok Kothari ◽  
Christopher A Miller ◽  
Jasreet Hundal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Survival Curve ◽  
Lymphoblastic Leukemia ◽  
Loss Of Function ◽  
Wild Type ◽  
Leukemic Transformation ◽  
Kaplan Meier ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Meier Survival Curve

Abstract Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A (Cancer Genome Atlas Research, N Engl J Med, 2013). We have recently shown that Dnmt3a is essential for normal hematopoietic stem cell (HSC) differentiation. Genetic ablation of Dnmt3a resulted in HSCs that showed diminished capacity for peripheral blood generation after serial transplantation (on a per-HSC basis), while phenotypically-defined HSCs accumulated in the bone marrow (Challen et al., Nature Genetics, 2012). Although this differentiation arrest was insufficient to cause overt disease, in these competitive transplants the presence of wild-type whole bone marrow may have suppressed malignant transformation of the mutant HSCs. Dnmt3a-null HSCs were less proliferative than counterpart control HSCs in this transplantation setting, suggesting that the cellular turnover threshold necessary to generate additional genetic and/or epigenetic lesions required for leukemogenesis was not achieved. To further understand the contribution of Dnmt3a loss-of-function in hematopoiesis, we performed non-competitive transplantation of Dnmt3a-null bone marrow. This forces the mutant HSCs to divide in vivoto regenerate the hematopoietic system following lethal irradiation, and should uncover any predispositions to transformation. Mice transplanted with Dnmt3a-null bone marrow in the absence of wild-type support cells succumbed principally to bone marrow failure (median survival 328 days) characteristic of myelodysplastic syndromes (MDS) with symptoms including anemia, neutropenia, bone marrow hypercellularity and splenomegaly with myeloid infiltration. 2/25 mice developed myeloid leukemia with >20% blasts in the blood and bone marrow. 4/25 primary mice succumbed to myeloproliferative disorders, some of which progressed to secondary leukemia after long latency. Exome sequencing was performed to identify co-operating mutations that drove leukemic transformation, and revealed c-Kit mutations found only in the Dnmt3a-null AML samples. As DNMT3A and KIT mutations can co-occur in AML and mastocytosis, we tested whether these two pathways could co-operate in vivo by ectopic introduction of c-Kit variants into hematopoietic progenitors followed by bone marrow transplantation (Figure 1). As previously reported, expression of c-KitD814V in wild-type cells lead to development of B-cell acute lymphoblastic leukemia (B-ALL). However, expression of c-KitD814V in a Dnmt3a-null background lead to acute leukemia with a much shorter latency (median survival 67 days), implicating a synergism between these pathways in vivo. Moreover, the absence of Dnmt3a also distorted the spectrum of leukemia resulting from enforced c-Kit signaling. While some of the mice transplanted with Dnmt3a-null c-KitD814V cells also succumbed to a B-ALL, 4/13 (31%) developed mastocytosis with involvement of myeloid blasts, and 4/13 (31%) mice developed a T-cell acute lymphoblastic leukemia (T-ALL). We show for the first time that these pathways can co-operate to accelerate transformation in vivo. This Dnmt3a/c-Kit disease model resembles the classical “two-hit” model of leukemogenesis in which one mutation in a hematopoietic progenitor cell inhibits differentiation (Dnmt3a loss-of-function), whilst another drives proliferation (c-Kit gain-of-function). Such mouse models present a unique opportunity to study the sequence of early events leading to HSC transformation following Dnmt3a-inactivation. Figure 1 Kaplan-Meier survival curve of mice transplanted with control or Dnmt3a-KO bone marrow progenitor cells transduced with a lentivirus expressing c-KitD814V. *** p <0.001. Figure 1. Kaplan-Meier survival curve of mice transplanted with control or Dnmt3a-KO bone marrow progenitor cells transduced with a lentivirus expressing c-KitD814V. *** p <0.001. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low Preoperative Mean Platelet Volume/Platelet Count Ratio Indicates Worse Prognosis in Non-Metastatic Renal Cell Carcinoma

2021 ◽  
Vol 10 (16) ◽  
pp. 3676
Author(s):  
Yu-Chiao Lin ◽  
Hau-Chern Jan ◽  
Horng-Yih Ou ◽  
Chien-Hui Ou ◽  
Che-Yuan Hu
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Platelet Count ◽  
Mean Platelet Volume ◽  
Renal Cell ◽  
Prognostic Value ◽  
Survival Curve ◽  
Platelet Volume ◽  
Kaplan Meier ◽  
Meier Survival Curve

Objectives: Multiple blood parameters are used to determine the prognosis of renal cell carcinoma (RCC). Mean platelet volume/platelet count (MPV/PC) ratio is related to disease progression in various cancers. Our study tried to evaluate the prognostic value of the MPV/PC ratio in RCC patients who underwent surgery. Methods: We retrospectively reviewed 89 patients who underwent radical or partial nephrectomy for RCC in a single institution. Baseline characteristics and MPV/PC ratios were analyzed. The optimal cut-off value of the MPV/PC ratio was determined by a receiver operating characteristic (ROC) curve, and our patients were divided into low and high MPV/PC ratio groups. The Kaplan–Meier survival curve and Cox proportional hazards model were applied for progression-free survival (PFS) and overall survival (OS) analyses. Harell’s C-index was used to compare the prognostic values of the MPV/PC ratio, MPV and PC. Results: Lower MPV/PC ratios were correlated with more advanced tumor stages and worse outcomes. The optimal cut-off value of the preoperative MPV/PC ratio was 0.034 (sensitivity 84.6%, specificity 56.6%). The Kaplan–Meier survival curve revealed that low MPV/PC ratios were associated with worse PFS (p = 0.007) and OS (p = 0.017). Multivariate analysis showed that low MPV/PC ratios were an independent unfavorable factor for PFS (p = 0.044) and OS (p = 0.015). Harell’s C-indexes showed that the prognostic value of the MPV/PC ratio was significantly better than MPV and PC (p < 0.001). Conclusion: Low MPV/PC ratios are an independent, unfavorable risk factor for disease progression and overall survival in patients undergoing surgery for RCC.

Dnmt3a Deletion Cooperates with the Flt3-ITD Mutation to Drive Leukemogenesis in a Murine Model

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3568-3568
Author(s):  
Jennifer L Poitras ◽  
Diane Heiser ◽  
Li Li ◽  
Bao Nguyen ◽  
Amy S. Duffield ◽  
...  
Keyword(s):  
Median Survival ◽  
Conflicts Of Interest ◽  
Survival Curve ◽  
Disease Onset ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Polycytidylic Acid ◽  
Kaplan Meier ◽  
Meier Survival Curve

Abstract Internal tandem duplications of the juxtamembrane domain of FLT3 (FLT3-ITD) are among the most common mutations in Acute Myeloid Leukemia (AML). Resulting in constitutive activation of the kinase, FLT3-ITD portends a particularly poor prognosis, with reduced overall survival and increased rates of relapse. We previously generated a knock-in mouse harboring an internal tandem duplication at the endogenous Flt3 locus, that develops a fatal myeloproliferative neoplasm (MPN), but fails to develop full blown leukemia, suggesting additional mutations are necessary for transformation. Global genomic sequencing studies have identified a substantial subset of patients in which FLT3-ITD and DNMT3A mutations are concomitantly present. Moreover, the co-occurrence of these mutations is significantly associated with adverse clinical outcomes (Patel JP, et al. NEJM. 2012;366:1079-89). Based on these observations, we investigated the potential cooperativity of FLT3-ITD and mutant DNMT3A to drive leukemogenesis using genetically engineered mouse strains. In accordance with mounting evidence that DNMT3A mutations result in a loss of function, we used a mouse model harboring floxed Dnmt3a alleles (Dnmt3af/f), and a lymphocyte specific Cre transgene (Mx1-Cre+), which is activated upon injection with Polyinosinic-polycytidylic acid (PiPC). We used a substrain of our Flt3-ITD knock-in mice, which retains a floxed Neomycin (Neo) selection cassette from the initial targeting (Flt3ITDneo/+), and reduces expression of the mutant allele until PiPC treatment. Mice were bred to contain both types of mutation and were injected with PiPC intraperitoneally at 8 weeks of age and monitored for disease development. Mice containing both the FLT3/ITD and Dnmt3af/f developed leukemias. Hempatopoietic tissues were examined morphologically and by flow cytometry. Interestingly, deletion of Dnmt3a significantly reduced median survival of Flt3-ITD mice in a dose-dependent manner, with median survival of 162 days and 260 days for Dnmt3af/f;Flt3ITDneo/+ and Dnmt3af/+;Flt3ITDneo/+, respectively (Figure 1). Both genotypes confer a significantly shorter survival time compared to Flt3ITDneo/+ alone controls, which have a median survival of 412 days. Moribund mice exhibited elevated white blood cell counts and splenomegaly, and developed a spectrum of diseases. As expected, Flt3ITDneo/+ mice solely developed MPN, while Dnmt3af/f;Flt3ITDneo/+ and Dnmt3af/+;Flt3ITDneo/+ developed a spectrum of neoplasms including MPN, T-ALL, and AML. Dnmt3a dosage influences the disease phenotype, as Dnmt3af/f;Flt3ITDneo/+ (n=18) develop T-ALL (46%), AML (31%), and MPN (23%), while Dnmt3af/+;Flt3ITDneo/+ mice (n=17) present with T-ALL (14%), T cell Lymphoma (14%), AML (43%), and MPN (29%). Recent work has demonstrated that Dnmt3a deletion in hematopoietic stem cells (HSC) promotes self renewal and expansion of the LT-HSC pool (Challan GA, et al. Nat Genet. 2011;44:23-31). Conversely, Flt3-ITD disrupts LT-HSC quiescence, resulting in depletion of this compartment (Heiser D & Chu SH, et al. Cell Stem Cell. 2012;11:346-58). To investigate if Dnmt3a deletion might restore or expand the LT-HSC compartment when combined with Flt3-ITD, we examined the bone marrow of mice 8 weeks post PiPC injection, and found that Dnmt3af/f;Flt3ITDneo/+ mice displayed an expansion of the LT-HSCs, ST-HSCs, and Multipotent Progenitors compared to wild type, Dnmt3af/f;Flt3+/+, and Flt3-ITD mice. The HSC populations of Dnmt3af/+;Flt3ITDneo/+ mice exhibit similar proportions compared with Flt3-ITD mice, with a modest increase in the MPP population. These results illustrate, for the first time, that Dnmt3a loss cooperates with Flt3-ITD to generate myriad hematopoietic neoplasms, including AML. In combination with Flt3-ITD, homozygous Dnmt3a knock-out results in reduced time to disease onset, LT-HSC expansion, and a higher incidence of T-ALL compared with loss of just one allele. The co-occurrence of FLT3 and Dnmt3a mutations in AML, as well as subsets of T-ALL, suggests the Dnmt3af/f;Flt3ITDneo/+ model may serve as a valuable resource for delineating effective therapeutic strategies in two clinically relevant contexts. Figure 1. Kaplan-Meier Survival Curve. Median survival: Dnmt3af/f;Flt3ITDneo/+ = 162 days (n=24), Dnmt3af/+;Flt3ITDneo/+ =260 days (n=20), Flt3ITDneo/+ = 412 days(n=12). Figure 1. Kaplan-Meier Survival Curve. Median survival: Dnmt3af/f;Flt3ITDneo/+ = 162 days (n=24), Dnmt3af/+;Flt3ITDneo/+ =260 days (n=20), Flt3ITDneo/+ = 412 days(n=12). Disclosures No relevant conflicts of interest to declare.

scholarly journals A Prognostic Autophagy-Related Long Non-coding RNA (ARlncRNA) Signature in Acute Myeloid Leukemia (AML)

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunxia Zhao ◽  
Yulu Wang ◽  
Famei Tu ◽  
Shuai Zhao ◽  
Xiaoying Ye ◽  
...  
Keyword(s):  
Cox Regression ◽  
Survival Curve ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Risk Groups ◽  
Gene Set Enrichment Analysis ◽  
Kaplan Meier ◽  
Non Coding Rna ◽  
Novel Biomarkers ◽  
Meier Survival Curve

BackgroundSome studies have proven that autophagy and lncRNA play important roles in AML. Several autophagy related lncRNA signatures have been shown to affect the survival of patients in some other cancers. However, the role of autophagy related lncRNA in AML has not been explored yet. Hence, this study aims to find an autophagy related lncRNA signature that can affect survival for AML patients.MethodA Pearson correlation analysis, a Kaplan–Meier survival curve, a univariate cox regression, and a multivariate cox regression were performed to establish an autophagy related lncRNA signature. A univariate cox regression, a multivariate cox regression, a Kaplan–Meier survival curve, and a ROC curve were applied to confirm if the signature is an independent prognosis for AML patients. The relationship between the signature and the clinical features was explored by using a T test. Gene Set Enrichment Analysis (GSEA) was used to investigate the potential tumor related pathways.ResultsA four-autophagy related lncRNA (MIR133A1HG, AL359715.1, MIRLET7BHG, and AL356752.1) signature was established. The high risk score based on signature was related to the short survival time of AML patients. The signature was an independent factor for the prognosis for AML patients (HR = 1.684, 95% CI = 1.324–2.142, P &lt; 0.001). The signature was correlated with age, leukocyte numbers, and FAB (M3 or non-M3). The P53, IL6/JAK/STAT3, TNF-α, INF-γ, and IL2/STAT5 pathways might contribute to the differences between the risk groups based on signature in AML.ConclusionThe four autophagy related lncRNAs and their signature might be novel biomarkers for predicting the survival of AML patients. Some biological pathways might be the potential mechanisms of the signature for the survival of AML patients.

scholarly journals Diagnostic and Prognostic Value of Presepsin in Patients with Non-Infectious Organ Failure, Sepsis, and Septic Shock: A Prospective Observational Study According to the Sepsis-3 Definitions

2021 ◽  
Author(s):  
Sukyo Lee ◽  
Juhyun Song ◽  
Dae Won Park ◽  
Hyeri Seok ◽  
Jae-hyung Cha ◽  
...  
Keyword(s):  
Septic Shock ◽  
Observational Study ◽  
Organ Failure ◽  
Prospective Observational Study ◽  
Survival Curve ◽  
Curve Analysis ◽  
Roc Curve Analysis ◽  
Kaplan Meier ◽  
Sepsis And Septic Shock ◽  
Meier Survival Curve

Abstract Background: Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. Early diagnosis of sepsis is challenging due to unknown sources of infection, and mortality prediction is usually complex. We aimed to investigate the clinical value of presepsin for discriminating sepsis from non-infectious organ failure and predicting mortality among sepsis patients in the emergency department (ED).Methods: This prospective observational study included 420 patients divided into three groups according to the Sepsis-3 definitions: non-infectious organ failure (n=142), sepsis (n=141), and septic shock (n=137). Blood samples for biomarker measurement of presepsin, procalcitonin, and C-reactive protein were drawn in the ED and biomarker levels were compared between the groups. Optimal cut-off values for presepsin to discriminate between the three clinical diagnoses were evaluated using receiver operating characteristic (ROC) curve analysis. We also performed ROC curve analysis for each biomarker as a predictor of mortality. After excluding non-infectious organ failure, we extracted the optimal cut-off value of presepsin to predict mortality associated with sepsis and septic shock and performed Kaplan–Meier survival curve analysis according to the cut-off value.Results: Presepsin levels (median [IQR]) were significantly higher in sepsis than in non-infectious organ failure (792 [450–1273] vs. 286 [170–417], p <0.001) and significantly higher in septic shock than in sepsis (1287 [589–2365] vs. 792 [450–1273], p=0.002). The optimal cut-off value for presepsin to discriminate between sepsis and non-infectious organ failure was 582 pg/mL (sensitivity, 70.1; specificity, 89.4; AUC, 0.877; p <0.001) and to discriminate between sepsis and septic shock was 1285 pg/mL (sensitivity, 50.4; specificity, 76.6; AUC, 0.618; p <0.001). The optimal cut-off value for presepsin for predicting 30-day mortality was 821 pg/mL (sensitivity, 68.9; specificity, 50.5; AUC, 0.605; p=0.005) in patients with sepsis and septic shock. Kaplan-Meier survival curve analysis showed that patients with higher presepsin levels (≥821 pg/mL) had significantly higher mortality than patients with lower presepsin levels (<821 pg/mL) (log-rank test; p=0.004). Conclusions: Presepsin levels could effectively differentiate sepsis from non-infectious organ failure and septic shock from sepsis. Presepsin levels could help clinicians predict mortality in patients with sepsis and septic shock.

The Incidence Prognosis and Risk Factors of Cognitive Impairment in Maintenance Haemodialysis Patients

2018 ◽  
Vol 47 (1-3) ◽  
pp. 101-108 ◽  
Author(s):  
Renhua Lu ◽  
Chenqi Xu ◽  
Yan Li ◽  
Ling Yu ◽  
Xinghua Shao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cognitive Impairment ◽  
Diastolic Pressure ◽  
Survival Curve ◽  
Maintenance Haemodialysis ◽  
Kaplan Meier ◽  
Education Status ◽  
Independent Risk Factors ◽  
Meier Survival Curve

Objective: To investigate the incidence and the prognosis of cognitive impairment (CI) and to find out the risk factors associated with the outcome in maintenance haemodialysis (MHD) patients. Methods: Enrolled the patients who met the criteria as below: MHD (≥3 months) patients before July 2014, ≥18 years old and could carry on the cognitive function test (Montreal Cognitive Assessment [MoCA]). All enrolled patients were divided into 2 groups: CI group (MoCA < 26) and non-CI group (MoCA ≥26). All patients were followed up for 36 months. The incidence, demography data, medical history, haemodialysis data, laboratory examination and prognosis of CI in haemodialysis patients were prospectively compared and analyzed. Multivariate logistic regression analysis was used to investigate the risk factors of CI. Kaplan-Meier survival curve was used for survival analysis. Results: In the present study, 219 patients were enrolled. The ratio of male to female was 1.46: 1. Age was 60.07 ± 12.44 and dialysis vintage was 100.79 ± 70.23 months. One hundred thirteen patients’ MoCA scores were lower than 26 were divided into CI group. Education status (OR 3.428), post-dialysis diastolic pressure (OR 2.234) and spKt/V (OR 1.982) were independent risk factors for CI in MHD patients. During the follow-up period, 15 patients died (13.2%) in the CI group and 5 died (4.72%) in the non-CI group (p < 0.05). The Kaplan-Meier survival curve analysis showed that the survival rate of patients with CI was lower than that of non-CI group in MHD patients during 3 years follow-up (p = 0.046). Conclusion: CI is one of the most common complications in MHD patients. The mortality is high in patients who had CI. Education status, post-dialysis diastolic pressure and spKt/V are independent risk factors for CI in MHD patients.

DDRE-26. INHIBITION OF PRMT5 SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi79-vi80
Author(s):  
Yesh Banasavadi ◽  
Sriya Namagiri ◽  
yoshihiro Otani ◽  
Shilpa Thammegowda ◽  
Hannah Sur ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Survival Curve ◽  
Oral Gavage ◽  
Cycle Progression ◽  
Arginine Methyltransferase ◽  
Tumor Bearing ◽  
Nsg Mice ◽  
Kaplan Meier ◽  
Meier Survival Curve

Abstract With limited effective therapeutic strategies, the prognosis for glioblastoma (GBM) is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. MEK inhibitors, including trametinib, are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-GBM efficacy of trametinib. Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. Trametinib treatment increased the activity of ERBB3 and AKT; With PRMT5 knockdown, the activity of both AKT and ERBB3 decreased significantly. But, inhibition of ERBB3 alone failed to block the trametinib-induced AKT activity suggesting that even though PRMT5 regulates the activity of both ERBB3 and AKT, the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib treated GBMNS is because of AKT inhibition alone. In vivo, PRMT5-depletion extended the survival of the tumor-bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit.

scholarly journals In Vitro Fatigue Resistance of Teeth Restored With Bulk Fill versus Conventional Composite Resin

2016 ◽  
Vol 27 (4) ◽  
pp. 452-457 ◽  
Author(s):  
Gabrielle Branco Rauber ◽  
Jussara Karina Bernardon ◽  
Luiz Clovis Cardoso Vieira ◽  
Hamilton Pires Maia ◽  
Françoá Horn ◽  
...  
Keyword(s):  
Fatigue Resistance ◽  
Composite Resin ◽  
Survival Curve ◽  
Maximum Force ◽  
Lower Percentage ◽  
Rank Test ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Meier Survival Curve

Abstract The aim of this study was to compare the fatigue resistance of restored teeth with bulk fill composite resin, conventional composite resin with incremental insertion and unprepared sound teeth. Twenty-eight extracted maxillary premolars were selected and divided into 4 groups based on composite resin and insertion technique: control (C), conventional composite resin with incremental insertion (I) and bulk fill composite resin with three (BF3) or single increment (BF1). The restored specimens were submitted to fatigue resistance test with a 5 Hz frequency. An initial application of 5,000 sinusoidal load cycles with a minimum force of 50 N and a maximum force of 200 N was used. Next, were applied stages of 30,000 load cycles with the maximum force increasing gradually: 400, 600, 800, 1000, 1200 and 1400 N. The test was concluded when 185,000 load cycles were achieved or the specimen failed. The fatigue resistance data were recorded for comparison, using the Kaplan-Meier survival curve and analyzed by log-rank test at 0.05 significance. Fractures were classified based on the position of the failure - above or below the cementoenamel junction (CEJ). Statistical analysis of the Kaplan-Meier survival curve and log-rank test showed a significant difference between groups (p=0.001). The fracture analysis demonstrated that only 28.58% of failures were below the CEJ in group C, while for groups I, BF1 and BF3 they were 42.85%, 85.71% and 85.71%, respectively. Teeth restored with composite bulk fill in both techniques present similar fatigue resistance values compared with those restored with a conventional incremental insertion of composite, while the fatigue strength values of unprepared sound teeth were higher. Furthermore, unprepared sound teeth showed a lower percentage of fractures below the CEJ.

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